U.S. patent number 5,561,140 [Application Number 08/419,799] was granted by the patent office on 1996-10-01 for substituted alicyclic amine-containing macrocyclic immunomodulators.
This patent grant is currently assigned to Abbott Laboratories. Invention is credited to Megumi Kawai, Jay R. Luly.
United States Patent |
5,561,140 |
Kawai , et al. |
October 1, 1996 |
**Please see images for:
( Certificate of Correction ) ** |
Substituted alicyclic amine-containing macrocyclic
immunomodulators
Abstract
Compounds having the formula ##STR1## and pharmaceutically
acceptable salts, esters, amides and prodrugs thereof, wherein one
of R.sup.104 and R.sup.105 is hydrogen, and the other of R.sup.104
and R.sup.105 is a group having the formula ##STR2## as well as
pharmaceutically compositions containing such compounds and methods
of immunomodulative therapy utilizing the same.
Inventors: |
Kawai; Megumi (Libertyville,
IL), Luly; Jay R. (Libertyville, IL) |
Assignee: |
Abbott Laboratories (Abbott
Park, IL)
|
Family
ID: |
26709095 |
Appl.
No.: |
08/419,799 |
Filed: |
April 11, 1995 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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341255 |
Nov 17, 1994 |
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99975 |
Jul 30, 1993 |
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32958 |
Mar 17, 1993 |
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Current U.S.
Class: |
514/291; 514/63;
540/456; 540/452 |
Current CPC
Class: |
C07D
498/18 (20130101); A61P 37/06 (20180101) |
Current International
Class: |
C07D
498/00 (20060101); C07D 498/18 (20060101); A61K
031/435 (); C07D 498/22 () |
Field of
Search: |
;540/452,456
;514/63,291 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Bond; Robert T.
Attorney, Agent or Firm: Crowley; Steven R. Steele; Gregory
W.
Parent Case Text
This application is a division of U.S. patent application Ser. No.
08/341,255, filed Nov. 17, 1994, which is a continuation of U.S.
patent application Ser. No. 08/099,975, filed Jul. 30, 1993, which
a continuation-in-part of the U.S. patent application Ser. No.
08/032,958, filed on Mar. 17, 1993, now abandoned.
Claims
What is claimed is:
1. A method for providing immunomodulation comprising administering
to a human in need of such treatment a therapeutically effective
amount of a compound having the formula: ##STR6## or a
pharmaceutically acceptable salt, ester, amide or prodrug thereof,
wherein
R.sup.100 is selected from the group consisting of hydrogen,
hydroxy, halogen, --OR.sup.13 and --OR.sub.14 ;
R.sup.101 is selected from the group consisting of methyl, ethyl,
allyl and propyl;
R.sup.102 is hydrogen and R.sup.103 is selected from the group
consisting of (a) hydrogen, (b) hydroxyl and (c) hydroxyl protected
by a hydroxy-protecting group selected from tri(C.sub.1 -C.sub.8
-loweralkyl)silyl, C.sub.1 -C.sub.8 -loweralkyldiarylsilyl,
triarylsilyl, tri(aryl-C.sub.1 -C.sub.12 -alkyl)silyl,
triphenylmethyl-dimethylsilyl, trimethylsilylethoxycarbonyl,
methylthiomethyoxyethoxycarbonyl, benzenesulfonylethoxycarbonyl,
trimethylsilylethoxymethyl and aryl-C(O)-- or, taken together,
R.sup.102 and R.sup.103 form a bond; and
one of R.sup.104 and R.sup.105 is hydrogen, and the other of
R.sup.104 and R.sup.105 is a group having the formula ##STR7##
where m and n are independently zero, one or two; X is selected
from the group consisting of oxygen, --S(O).sub.s -- where s is
zero, one or two, --N(R.sup.1)-- and --C(R.sup.2)(R.sup.2')--, or
is absent; and
R.sup.3, R.sup.4 and R.sup.5 are independently selected from the
group consisting of
(a) hydrogen;
(b) C.sub.1 -C.sub.12 -alkyl;
(c) halo-C.sub.1 -C.sub.12 -alkyl;
(d) C.sub.3 -C.sub.8 -cycloalkyl;
(e) C.sub.3 -C.sub.8 -cycloalkyl-C.sub.1 -C.sub.8 -alkyl;
(f) C.sub.2 -C.sub.12 -alkenyl;
(g) C.sub.2 -C.sub.12 -alkynyl;
(h) hydroxy-C.sub.1 -C.sub.8 -alkyl;
(i) hydroxyl-C.sub.1 -C.sub.8 -alkoxy-C.sub.1 -C.sub.12 -alkyl;
(j) aryl substituted by R.sup.6, R.sup.7 and R.sup.8 wherein
R.sup.6, R.sup.7 and R8 are defined as below;
(j') aryl-C.sub.1 -C.sub.12 -alkyl substituted by R.sup.6, R.sup.7
and R.sup.8 wherein R.sup.6, R.sup.7 and R8 are defined as
below;
(k) C.sub.1 -C.sub.8 -alkoxycarbonyl;
(l) C.sub.1 -C.sub.8 -alkoxycarbonyl-C.sub.1 -C.sub.12 -alkyl;
(m) carboxy-C.sub.1 -C.sub.8 -alkyl;
(n) aminoalkyl of the formula (R.sup.403)(R.sup.404)N--C.sub.1
-C.sub.8 -alkyl wherein R.sup.403 and R.sup.404 are independently
selected from hydrogen, C.sub.1 -C.sub.8 -alkyl, aryl and
aryl-C.sub.1 -C.sub.12 -alkyl or R.sup.403 and R.sup.404, taken
together, are --(CH.sub.2).sub.bb -- wherein bb is 2-6;
(o) C.sub.1 -C.sub.12 -thiolalkyl;
(p) C.sub.1 -C.sub.12 -alkyl-C(O)-- or aryl-C(O)--;
(q) heterocyclic;
(r) (heterocyclic)-C.sub.1 -C.sub.12 -alkyl;
(s) (heterocyclic)-C.sub.1 -C.sub.12 -alkylamino-C.sub.1 -C.sub.8
-alkyl;
(u) N-mono-C.sub.1 -C.sub.12 -alkylamino-C.sub.1 -C.sub.8 -alkyl or
N-mono-C.sub.3 -C.sub.8 -cycloalkylamino-C.sub.1 -C.sub.8
-alkyl;
(u') N,N-di-(C.sub.1 -C.sub.12 -alkyl)amino-C.sub.1 -C.sub.8 -alkyl
or N,N-di-(C.sub.3 -C.sub.8 -cycloalkyl)amino-C.sub.1 -C.sub.8
-alkyl;
(v) N-mono-C.sub.1 -C.sub.12 -alkylcarboxamido-C.sub.1 -C.sub.8
-alkyl;
(v') N,N -di-(C.sub.1 -C.sub.12 -alkyl)carboxamido-C.sub.1 -C.sub.8
-alkyl;
(w) N-monoarylcarboxamido-C.sub.1 -C.sub.8 -alkyl;
(w') N,N-diarylcarboxamido-C.sub.1 -C.sub.8 -alkyl;
(x) formyl;
(x') protected formyl selected from dimethylacetal, diethylacetal,
bis-(2,2,2-trichloroethyl)acetal, dibenzylacetal, 1,3-dioxanyl,
5-methylene-1,3-dioxanyl, 5,5-dibromo-1,3-dioxanyl,
O-methyl-S-2-(methythiol)ethyl acetal and 1,3-oxathiolanyl;
(z) (heterocyclic)-C.sub.2 -C.sub.12 -alkenyl; and
(aa) (heterocyclic)-C.sub.2 -C.sub.12 -alkynyl; or, taken together,
R.sup.3 and R.sup.5 form a methylene radical --CH.sub.2 --;
R.sup.1 is selected from the group consisting of
(a) hydrogen;
(b) C.sub.1 -C.sub.12 -alkyl;
(c) halo-C.sub.1 -C.sub.12 -alkyl;
(d) C.sub.3 -C.sub.8 -cycloalkyl;
(e) C.sub.3 -C.sub.8 -cycloalkyl-C.sub.1 -C.sub.8 -alkyl;
(f) C.sub.2 -C.sub.12 -alkenyl;
(g) C.sub.2 -C.sub.12 -alkynyl;
(h) hydroxy-C.sub.1 -C.sub.8 -alkyl;
(i) hydroxyl-C.sub.1 -C.sub.8 -alkoxy-C.sub.1 -C.sub.12 -alkyl;
(j) aryl substituted by R.sup.6, R.sup.7 and R.sup.8 wherein
R.sup.6, R.sup.7 and R8 are independently defined as below;
(j') aryl-C.sub.1 -C.sub.12 -alkyl substituted by R.sup.6, R.sup.7
and R.sup.8 wherein R.sup.6, R.sup.7 and R8 are independently
defined as below;
(k) C.sub.1 -C.sub.8 -alkoxycarbonyl;
(l) C.sub.1 -C.sub.8 -alkoxycarbonyl-C.sub.1 -C.sub.12 -alkyl;
(m) carboxy-C.sub.1 -C.sub.8 -alkyl;
(n) aminoalkyl of the formula (R.sup.403)(R.sup.404)N--C.sub.1
-C.sub.8 -alkyl wherein R.sup.403 and R.sup.404 are independently
defined as above;
(o) C.sub.1 -C.sub.12 -thiolalkyl;
(p) --S(O).sub.x --R.sup.9 where x is one or two and R.sup.9 is
selected from the group consisting of C.sub.1 -C.sub.12 -alkyl,
aryl, and aryl-C.sub.1 -C.sub.12 -alkyl;
(p') C.sub.1 -C.sub.12 -alkyl-C(O)-- or aryl-C(O)--;
(q) heterocyclic;
(r) (heterocyclic)-C.sub.1 -C.sub.12 -alkyl;
(s) (heterocyclic)-C.sub.1 -C.sub.12 -alkylamino-C.sub.1 -C.sub.8
-alkyl;
(u) N-mono-C.sub.1 -C.sub.12 -alkylamino-C.sub.1 -C.sub.8 -alkyl or
N-mono-C.sub.3 -C.sub.8 -cycloalkylamino-C.sub.1 -C.sub.8
-alkyl;
(u') N,N-di-(C.sub.1 -C.sub.12 -alkyl)amino-C.sub.1 -C.sub.8 -alkyl
or N,N-di-(C.sub.3 -C.sub.8 -cycloalkyl)amino-C.sub.1 -C.sub.8
-alkyl;
(v) N-mono-C.sub.1 -C.sub.12 -alkylcarboxamido-C.sub.1 -C.sub.8
-alkyl;
(v') N,N -di-(C.sub.1 -C.sub.12 -alkyl)carboxamido-C.sub.1 -C.sub.8
-alkyl;
(w) N-monoarylcarboxamido-C.sub.1 -C.sub.8 -alkyl;
(w') N,N-diarylcarboxamido-C.sub.1 -C.sub.8 -alkyl;
(x) formyl;
(x') protected formyl selected from dimethylacetal, diethylacetal,
bis-(2,2,2-trichloroethyl)acetal, dibenzylacetal, 1,3-dioxanyl,
5-methylene-1,3-dioxanyl, 5,5-dibromo-1,3-dioxanyl,
O-methyl--S-2-(methythiol)ethyl acetal and 1,3-oxathiolanyl;
(y) --P(O)(OR.sup.10)(OR.sup.10') where R.sup.10 and R.sup.10' are
independently selected from the group consisting of C.sub.1
-C.sub.8 -loweralkyl, aryl-C.sub.1 -C.sub.12 -alkyl and aryl;
(z) (heterocyclic)-C.sub.2 -C.sub.12 -alkenyl;
(aa) (heterocyclic)-C.sub.2 -C.sub.12 -alkynyl;
(bb) --NHC(O)NH.sub.2 ;
(cc) nitro; and
(dd) polyhydroxyl-C.sub.1 -C.sub.12 -alkyl;
R.sup.2 and R.sup.2' are independently selected from the group
consisting of hydrogen, hydroxy, hydroxy-C.sub.1 -C.sub.8 -alkyl,
R.sup.402 C(O)N(R.sup.401)--C.sub.1 -C.sub.8 -alkyl wherein
R.sup.401 and R.sup.402 are independently selected from hydrogen,
C.sub.1 -C.sub.8 -alkyl, aryl, aryl-C.sub.1 -C.sub.12 -alkyl and
halo-C.sub.1 -C.sub.12 -alkyl or R.sup.401 and R.sup.402, taken
together, are --(CH.sub.2).sub.aa -- wherein aa is 2-6,
--C(O)NH(C.sub.1 -C.sub.8 -alkyl), --C(O)N(C.sub.1 -C.sub.8
-alkyl)(C.sub.1 -C.sub.8 -alkyl), pyrrolidin-1-yl and
piperidin-1-yl; or, taken together, R.sup.2 and R.sup.2' are a
divalent radical selected from the group consisting of oxo, thiooxo
and --O(CH.sub.2).sub.i O--, where i is two, three or four;
R.sup.6, R.sup.7 and R.sup.8 are independently selected from the
group consisting of
(i) hydrogen;
(ii) --(C.sub.1 -to-C.sub.7 alkyl);
(iii) --(C.sub.2 -to-C.sub.6 alkenyl);
(iv) halogen;
(v) --(CH.sub.2).sub.m NR.sup.11 R.sup.11' where m is an integer
between one and ten, and R.sup.11 and R.sup.11' are independently
selected from the group consisting of hydrogen, C.sub.1 -C.sub.12
-alkyl, aryl, aryl-C.sub.1 -C.sub.12 -alkyl, heterocyclic,
(heterocyclic)-C.sub.1 -C.sub.12 -alkyl, (heterocyclic)-C.sub.2
-C.sub.12 -alkenyl and (heterocyclic)-C.sub.2 -C.sub.12
-alkynyl;
(vi) --CN;
(vii) --CHO;
(viii) mono-, di-, tri- or perhalogenated --C.sub.1 -C.sub.12
-alkyl;
(ix) --S(O).sub.s R.sup.11 where s is zero, one or two and R.sup.11
is defined as above;
(x) --C(O)NR.sup.11 R.sup.11' wherein R.sup.11 and R.sup.11' are
defined as above;
(xi) --(CH.sub.2).sub.m OR.sup.11 wherein R.sup.11 is defined as
above;
(xii) --CH(OR.sup.12)(OR.sup.12'), where R.sup.12 and R.sup.12' are
independently --(C.sub.1 -to-C.sub.3 alkyl) or, taken together,
form an ethylene or propylene bridge;
(xiii) --(CH.sub.2).sub.m OC(O)R.sup.11 wherein R.sup.11 is defined
as above;
(xiv) --(CH.sub.2).sub.m C(O)OR.sup.11 wherein R.sup.11 is defined
as above;
(xv) --OR.sup.13, where R.sup.13 is selected from the group
consisting of
(A) --PO(OH)OH,
(B) --SO.sub.3 H, and
(C) --C(O)(CH.sub.2).sub.m C(O)OH;
(xvi) --S(O).sub.t NR.sup.11 R.sup.11', where t is one or two and
R.sup.11 and R.sup.11' are defined as above;
(xvii) --NO.sub.2 ;
(xviii) --N3; and
(xviv) guanidino optionally substituted by a radical selected from
the group consisting of C.sub.1 -C.sub.8 -loweralkyl, aryl, C.sub.1
-C.sub.12 -alkyl-C(O)--, aryl-C(O)--, arylsulfonyl, C.sub.1
-C.sub.8 -alkoxycarbonyl, aryl-C.sub.1 -C.sub.8 -alkoxycarbonyl,
aryloxycarbonyl and C.sub.1 -C.sub.12 -alkylsulfonyl,
or any two adjacent R.sup.6, R.sup.7 and R.sup.8 and the atoms to
which they are attached form a carbocyclic or heterocyclic ring
having between 5 and 7 ring atoms; and
R.sup.14 is selected from the group consisting of (i) C.sub.1
-C.sub.12 -alkyl-C(O)-- or aryl-C(O)--; (ii) --(C.sub.1 -to-C.sub.7
alkyl); (iii) --(C.sub.2 -to-C.sub.6 alkenyl); (vi)
--(CH.sub.2).sub.m NR.sup.11 R.sup.11', where m is an integer
between one and ten and R.sup.11 and R.sup.11' are independently
defined as above; (v) --S(O).sub.s R.sup.11, where s selected from
the group consisting of zero, one and two and R.sup.11 is
independently defined as above; (vi) --C(O)NR.sup.11 R.sup.11'
wherein R.sup.11 and R.sup.11' are independently defined as above;
(vii) --(CH.sub.2).sub.m OR.sup.11 wherein R.sup.11 is
independently defined as above; (viii) --CH(OR.sup.12)(OR.sup.12')
wherein R.sup.12 and R.sup.12' are independently defined as above;
(ix) --(CH.sub.2).sub.m OC(O)R.sup.11 wherein R.sup.11 is
independently defined as above; (x) --(CH.sub.2).sub.m
C(O)OR.sup.11 wherein R.sup.11 is independently defined as above;
and (xi) --S(O).sub.t NR.sup.11 R.sup.11', where t is selected from
the group consisting of one and two and R.sup.11 and R.sup.11' are
independently defined as above; wherein at each occurrence aryl is
independently selected from phenyl, 1-naphthyl, 2-naphthyl,
fluorenyl, (1,2)-dihydronaphthyl, (1,2,3,4-)-tetrahydronaphthyl,
indenyl and indanyl; and at each occurrence heterocyclic is
independently selected from the group consisting of pyrrolyl,
pyrrolidinyl, pyrazolyl, pyrazolidinyl, cytosinyl, thiocytosinyl,
imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl,
pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl,
xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracilyl,
isoxazolyl, isoxazolidinyl, morpholinyl, indolyl, quinolinyl,
uracilyl, urazolyl, uricyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, isoquinolinyl, thyminyl, benzimidazolyl,
benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
2. The method of claim 1 wherein R.sup.100 is hydrogen.
3. The method of claim 1 wherein R.sup.101 is ethyl.
4. The method of claim 1 wherein R.sup.102 is hydrogen.
5. The method of claim 1 wherein R.sup.103 is selected from the
group consisting of hydrogen and hydroxyl.
6. The method of claim 1 wherein R.sup.103 is hydroxyl protected by
a hydroxy-protecting group selected from tri(C.sub.1 -C.sub.8
-loweralkyl)silyl, C.sub.1 -C.sub.8 -loweralkyldiarylsilyl,
triarylsilyl, tri(arylC.sub.1 -C.sub.12 -alkyl)silyl,
triphenylmethyl-dimethylsilyl, trimethylsilylethoxycarbonyl,
methylthiomethyoxyethoxycarbonyl, benzenesulfonylethoxycarbonyl,
trimethylsilylethoxymethyl and aryl-C(O)--.
7. The method of claim 1 wherein R.sup.104 is hydrogen.
8. The method of claim 1 wherein m and n are integers independently
selected from the group consisting of zero and one.
9. The method of claim 1 wherein R.sup.105 is a radical having the
formula ##STR8## wherein X is selected from the group consisting of
--S(O).sub.s --, --C(R.sup.2)(R.sup.2')-- and --N(R.sup.1)--
wherein n, m, s, R.sup.1, R.sup.2, R.sup.2', R.sup.3, R.sup.4 and
R.sup.5 are as defined therein.
10. The method of claim 9 wherein X is selected from the group
consisting of --S(O).sub.s --, --C(R.sup.2)(R.sup.2')-- and
--N(R.sup.1)-- wherein s, R.sup.1, R.sup.2 and R.sup.2' are as
defined therein.
11. The method of claim 9 wherein R.sup.1, R.sup.3, R.sup.4 and
R.sup.5 are independently selected from the group consisting of
(a) hydrogen;
(b) C.sub.1 -C.sub.12-alkyl;
(c) C.sub.3 -C.sub.8 -cycloalkyl;
(d) C.sub.3 -C.sub.8 -cycloalkyl-C.sub.1 -C.sub.8 -alkyl;
(e) hydroxy-C.sub.1 -C.sub.8 -alkyl;
(f) hydroxyl-C.sub.1 -C.sub.8 -alkoxy-C.sub.1 -C.sub.12 -alkyl;
(g) aryl substituted by R.sup.6, R.sup.7 and R.sup.8 ;
(h) aryl-C.sub.1 -C.sub.12 -alkyl substituted by R.sup.6, R.sup.7
and R.sup.8 ;
(i) C.sub.1 -C.sub.8 -alkoxycarbonyl;
(j) C.sub.1 -C.sub.8 -alkoxycarbonyl-C.sub.1 -C.sub.12 -alkyl;
(k) carboxy-C.sub.1 -C.sub.8 -alkyl;
(l) aminoalkyl of the formula (R.sup.403)(R.sup.404)N-C.sub.1
-C.sub.8 -alkyl wherein R.sup.403 and R.sup.404 are independently
selected from hydrogen, C.sub.1 -C.sub.8 -alkyl, aryl and
aryl-C.sub.1 -C.sub.12 -alkyl or R.sup.403 and R.sup.404, taken
together, are --(CH.sub.2).sub.bb -- wherein bb is 2-6;
(m) C.sub.1 -C.sub.12 -thioalkyl;
(n) heterocyclic;
(o) (heterocyclic)-C.sub.1 -C.sub.12 -alkyl;
(p) (heterocyclic)-C.sub.1 -C.sub.12 -alkylamino-C.sub.1 -C.sub.8
-alkyl;
(q) C.sub.1 -C.sub.12 -alkyl-C(O)-- or aryl-C(O)--;
(r) N-mono- or N,N-dialkylaminoalkyl;
(s) N-mono- or N,N-dialkyl-carboxamidoalkyl;
(t) N-mono- or N,N-diarylcarboxamidoalkyl; and
(u) formyl.
12. The method of claim 9 wherein X is selected from the group
consisting of --N(R.sup.1)-- and --C(R.sup.2)(R.sup.2')-- wherein
R.sup.1, R.sup.2 and R.sup.2' are as defined therein.
13. A method for providing immunomodulation comprising
administering to a human in need of such treatment a
therapeutically effective amount of a compound having the formula:
##STR9## wherein one of R.sup.104 and R.sup.105 is hydrogen, and
the other of R.sup.104 and R.sup.105 is a group having the formula
##STR10## wherein (a) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl;
R.sup.102 .dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104
.dbd.H; m=0; n=1; R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X
is --(CH.sub.3)N--;
(b) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X is
--(benzyl)N--;
(c) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X is
--(phenyl)N--;
(d) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(tert-butyloxycarbonyl)N--;
(e) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--[4-nitrobenzyl]N--.
(f) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(.beta.-naphthylmethyl)N--.
(g) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X.dbd.--CH.sub.2
--;
(h) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X is
--(formyl)N--;
(i) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X is
--C(R.sup.2)(R.sup.2')-- wherein R.sup.2 and R.sup.2' taken
together form --O(CH.sub.2).sub.i O-- wherein i=2;
(j) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(2-hydroxyethyl)N--;
(k) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X.dbd.oxygen;
(l) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(2-(2-hydroxyethoxy)ethyl)N--;
(m) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(2-pyridyl)N--
(n) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(2-pyrimidyl)N--;
(o) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X.dbd.--NH--;
(p) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.1-(-pyrrolidinocarbonylmethyl)N--;
(q) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(1-morpholinocarbonylmethyl)N--;
(r) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X is
--(cyclopentyl)N--;
(s) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(piperonyl)N--.
(t) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(4-acetylphenyl)N--;
(u) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X is
--C(R.sup.2)(R.sup.2')-- wherein R.sup.2 .dbd.N-pyrrolidino and
R.sup.2' .dbd.H;
(v) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(ethoxycarbonyl)N--;
(w) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(acetyl)N--;
(x) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and
X.dbd.--(iso-propylaminocarbonylmethyl)N--;
(y) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; and X is
--C(R.sup.2)R.sup.2')-- wherein R.sup.2 .dbd.hydroxy and R.sup.2'
.dbd.H;
(z) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3 .dbd.hydroxymethyl; and X is
--CH.sub.2 --;
(aa) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3 .dbd.hydroxymethyl; and X is
--CH.sub.2 --;
(bb) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.4 .dbd.hydroxymethyl; and X is
--CH.sub.2 --;
(cc) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3 .dbd.2-hydroxyethyl; and X is
--CH.sub.2 --;
(dd) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.4 .dbd.hydroxy; and X is
--CH.sub.2 --; or
(ee) R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.104 .dbd.H; m=0; n=1;
R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3 .dbd.hydroxymethyl; and X is
--CH.sub.2 --;
or a pharmaceutically acceptable salt, ester, amide or prodrug
thereof.
Description
FIELD OF THE INVENTION
The present invention relates to novel chemical Compounds having
immunomodulatory activity, and in particular to macrolide
immunosuppressants. More particularly, the invention relates to
semisynthetic analogs of ascomycin and FK-506, means for their
preparation, pharmaceutical compositions containing such compounds
and methods of treatment employing the same.
BACKGROUND OF THE INVENTION
The compound cyclosporine (cyclosporin A) has found wide use since
its introduction in the fields of organ transplantation and
immunomodulation, and has brought about a significant increase in
the success rate for transplantation procedures. Unsatisfactory
side-effects associated with cyclosporine, however, such as
nephrotoxicity, have led to a continued search for
immunosuppressant compounds having improved efficacy and
safety.
Recently, several classes of macrocyclic compounds having potent
immunomodulatory activity have been discovered. Okuhara et al., in
European Patent Application No. 184162, published Jun. 11, 1986,
disclose a number of macrocyclic compounds isolated from the genus
Streptomyces. Immunosuppressant FK-506, isolated from a strain of
S. tsukubaensis, is a 23-membered macrocyclic lactone represented
by formula la, below. Other related natural products, such as
FR-900520 (1b) and FR-900523 (1c), which differ from FK-506 in
their alkyl substituent at C-21, have been isolated from S.
hygroscopicus yakushimnaensis. Yet another analog, FR-900525,
produced by S. tsukubaensis, differs from FK-506 in the replacement
of a pipecolic acid moiety with a proline group.
FR-900520, also known as ascomycin, has been previously disclosed
by Arai et al. in U.S. Pat. No. 3,244,592, issued Apr. 5, 1966,
where the compound is described as an antifungal agent. Monaghan,
R. L., et al., on the other hand, describe the use of ascomycin as
an immunosuppressant in European Patent Application No. 323865,
published Jul. 12, 1989.
Although the immunosuppressive activity of FK-506 has been
clinically confirmed, toxicity in mammals has limited its utility.
The activity of FK-506 has, however, prompted efforts to discover
novel analogs of FK-type compounds which possess superior
properties. These efforts include the isolation of new fermentation
products, the microbial transformation of existing chemical
entities, the chemical modification of these macrocycles, and the
synthesis of hybrid species derived from smaller synthetic
fragments. ##STR3##
Fermentation products of FK-type compounds include C-21-epi
derivatives of FK-506; a 31-demethylated derivative of FK-506; 3
1-oxo-FK-506; and compounds derived from FK-506, FR-900523 and
FR-900525 which are characterized by the introduction of
hydroxy-protecting groups, formation of a double bond by
elimination of water between carbons 23 and 24, oxidation of the
hydroxy group at carbon 24 to the ketone, and reduction of the
allyl sidechain at carbon 21 via hydrogenation. Other published
derivatives include those derived from FK-506 and FR-900520 where
the lactone ring is contracted to give a macrocyclic ring
containing two fewer carbons. Several microbial transformations of
FK-type compounds at carbon 13 have been published, such as the
microbial demethylation of FR-900520 to form the bis-demethylated
13,31-dihydroxy ring-rearranged derivative of FR-900520; the
microbial mono-demethylation of FK-506 and FR-900520, respectively;
and the microbial demethylation of FR-900520 at C-31, as well as a
number of other macrocyclic microbial transformation products.
Numerous chemical modifications of the FK-type compounds have been
attempted. These include the preparation of small synthetic
fragments of FK-type derivatives; a thermal rearrangement of a
variety of derivatives of FK-506 which expands the macrocyclic ting
by two carbons; and modifications which include methyl ether
formation at C-32 and/or C-24, oxidation of C-32 alcohol to the
ketone, and epoxide formation at C-9.
Although some of these modified compounds exhibit immunosuppressive
activity, the need remains for macrocyclic immunosuppressants which
do not have the serious side effects frequently associated with
immunosuppressant therapy. Accordingly, one object of the invention
is to provide novel semisynthetic macrolides which possess the
desired immunomodulatory activity but which may be found to
minimize untoward side effects.
Another object of the present invention is to provide synthetic
processes for the preparation of such compounds from starting
materials obtained by fermentation, as well as chemical
intermediates useful in such synthetic processes.
A further object of the invention is to provide pharmaceutical
compositions containing, as an active ingredient, one of the above
compounds. Yet another object of the invention is to provide a
method of treating a variety of disease states, including
post-transplant tissue rejection and autoimmune disfunction.
SUMMARY OF THE INVENTION
In one aspect of the present invention are disclosed compounds
having the formula ##STR4## and the pharmaceutically acceptable
salts, esters, amides and prodrugs thereof, wherein
R.sup.100 is hydrogen, hydroxy, halogen, --OR.sup.13 or --OR.sup.14
;
R.sup.101 is methyl, ethyl, allyl or propyl;
R.sup.102 is hydrogen and R.sup.103 is selected from (a) hydrogen,
(b) hydroxyl and (c) hydroxyl protected by a hydroxy-protecting
group or, taken together, R.sup.102 and R.sup.103 form a bond;
and
one of R.sup.104 and R.sup.105 is hydrogen, and the other of
R.sup.104 and R.sup.105 is a group having the formula ##STR5##
where m and n are independently zero, one or two;
X is selected from the group consisting of oxygen, --S(O).sub.s --
where s is zero, one or two, --N(R.sup.1)-- and
--C(R.sup.2)(R.sup.2')--, or is absent; and
R.sup.3, R.sup.4 and R.sup.5 are independently selected from the
group consisting of (a) hydrogen; (b) alkyl; (c) haloalkyl; (d)
cycloalkyl; (e) cycloalkylalkyl; (f) alkenyl; (g) alkynyl; (h)
hydroxyalkyl; (i) hydroxylalkoxyalkyl; (j) aryl substituted by
R.sup.6, R.sup.7 and R.sup.8 ; (j') arylalkyl substituted by
R.sup.6, R.sup.7 and R.sup.8 ; (k) alkoxycarbonyl; (l)
alkoxycarbonylalkyl; (m) carboxyalkyl; (n) aminoalkyl; (o)
thiolalkyl; (q) heterocyclic; (r) (heterocyclic)alkyl; (s)
(heterocyclic)alkylaminoalkyl; (p) acyl; (u) N-mono- or
N,N-dialkylaminoallcyl; (v) N-mono- or N,N-dialkylcarboxamidoalkyl;
(w) N-mono- or N,N-diarylcarboxamidoalkyl; (x) formyl; (x')
protected formyl; (z) (heterocyclic)alkenyl; and (aa)
(heterocyclic)alkynyl. Alternatively, R.sup.3 and R.sup.5, when
taken together, may form a methylene --CH.sub.2 -- so that the
group of Formula (II) becomes a bicyclic radical.
In the above, R.sup.1 is selected from the group consisting of (a)
hydrogen; (b) alkyl; (c) haloalkyl; (d) cycloalkyl; (e)
cycloalkylalkyl; (f) alkenyl; (g) alkynyl; (h) hydroxyalkyl; (i)
hydroxylalkoxyalkyl; (j) aryl substituted by R.sup.6, R.sup.7 and
R.sup.8 ; (j') arylalkyl substituted by R.sup.6, R.sup.7 and
R.sup.8 ; (k) alkoxycarbonyl; (1) alkoxycarbonylalkyl; (m)
carboxyalkyl; (n) aminoalkyl; (o) thiolalkyl; (p) --S(O).sub.x
--R.sup.9, wherein x is one or two and R.sup.9 is selected from the
group consisting of alkyl, aryl, and arylalkyl; (q) heterocyclic;
(r) (heterocyclic)alkyl; (s) (heterocyclic)alkylaminoakkyl; (t)
acyl; (u) N-mono- or N,N-dialkylaminoalkyl; (v) N-mono- or
N,N-dialkylcarboxamidoalkyl; (w) N-mono- or
N,N-diarylcarboxamidoalkyl; (x) formyl; (x') protected formyl; (y)
--P(O)(OR.sup.10)(OR.sup.10') where R.sup.10 and R.sup.10' are
independently selected from the group consisting of loweralkyl,
arylalkyl and aryl; (z) (heterocyclic)alkenyl; (aa)
(heterocyclic)-alkynyl; (bb) urea; (cc) nitro; and (dd)
polyhydroxylalkyl.
R.sup.2 and R.sup.2' in the above are independently selected from
the group consisting of hydrogen, hydroxy, hydroxyalkyl,
amidoalkyl, N-alkylcarboxamido, N,N-dialkylamino, pyrrolidin-1-yl
and piperidin-1-yl; or, taken together, R.sup.2 and R.sup.2' are
oxo, thiooxo or --O(CH.sub.2).sub.i O--, where i is two, three or
four.
R.sup.6, R.sup.7 and R.sup.8 in the above are independently
selected from (i) hydrogen; (ii) --(C.sub.1 -to-C.sub.7 alkyl);
(iii) --(C.sub.2 -to-C.sub.6 alkenyl); (iv) halogen; (v)
--(CH.sub.2).sub.m NR.sup.11 R.sup.11' where m is an integer
between one and ten, inclusive, and R.sup.11 and R.sup.11' are
independently selected from the group consisting of hydrogen,
alkyl, aryl, arylalkyl, heterocyclic, (heterocyclic)alkyl,
(heterocyclic)alkenyl and (heterocyclic)alkynyl; (vi) --CN; (vii)
--CHO; (viii) mono-, di-, tri- or perhalogenated alkyl; (ix)
--S(O).sub.s R.sup.11 where s is zero, one or two; (x)
--C(O)NR.sup.11 R.sup.11' ; (xi) --(CH.sub.2).sub.m OR.sup.11 ;
(xii) --CH(OR.sup.12)(OR.sup.12'), where R.sup.12 and R.sup.12' are
independently --(C.sub.1 -to-C.sub.3 alkyl) or, taken together,
form an ethylene or propylene bridge; (xiii) --(CH.sub.2).sub.m
OC(O)R.sup.11 ; (xiv) --(CH.sub.2).sub.m C(O)OR.sup.11 ; (xv)
--OR.sup.13 ; (xvi) --S(O).sub.t NR.sup.11 R.sup.11', where t is
one or two; (xvii) --NO.sub.2 ; (xviii) --N.sub.3 ; and (xviv)
guanidino optionally substituted by a radical selected from the
group consisting of loweralkyl, aryl, acyl, arylsulfonyl,
alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl and
alkylsulfonyl. Alteratively, any two adjacent R.sup.6, R.sup.7 and
R.sup.8 and the atoms to which they are attached may form a
carbocyclic or heterocyclic ring having 5, 6 or 7 ting atoms which
optionally include one or two additional heteroatoms independently
selected from the group consisting of --O--, --S(O).sub.s -- where
s is zero, one or two, and --NR.sup.11 --.
R.sup.13 in the above is selected from (i) --PO(OH)O.sup.- M.sup.+,
(ii) --SO.sub.3.sup.- M.sup.+, and (iii) --C(O)(CH.sub.2).sub.m
C(O)O.sup.- M.sup.+, where M.sup.+ is a proton or a positively
charged inorganic or organic counterion, and m is an integer
between one and ten, inclusive.
R.sup.14 in the above is selected from the group consisting of (i)
acyl; (ii) --(C.sub.1 -to-C.sub.7 alkyl); (iii) --(C.sub.2
-to-C.sub.6 alkenyl); (vi) --(CH.sub.2).sub.m NR.sup.11 R.sup.11',
where m is an integer between one and ten, inclusive; (v)
--S(O).sub.s R.sup.11, where s is zero, one or two; (vi)
--C(O)NR.sup.11 R.sup.11' ; (vii) --(CH.sub.2).sub.m OR.sup.11 ;
(viii) --CH(OR.sup.12)(OR.sup.12'); (ix) --(CH.sub.2).sub.m
OC(O)R.sup.11 ; (x) --(CH.sub.2).sub.m C(O)OR.sup.11 ; and (xi)
--S(O).sub.t NR.sup.11 R.sup.11', where t is one or two;
In another aspect of the present invention are disclosed
pharmaceutical compositions, comprising a compound of the invention
in combination with a pharmaceutically acceptable cartier.
In a further aspect of the present invention is disclosed a method
for treating a patient in need of immunomodulative therapy,
comprising administering to such a patient a therapeutically
effective amount of a compound of the invention for such time as is
necessary to obtain the desired therapeutic effect.
DETAILED DESCRIPTION OF THE INVENTION
Among the preferred compounds of the present invention are those
having formula (I) in which:
m and n are independently zero or one;
X is selected from the group consisting of --S(O).sub.s -- and
--N(R.sup.1)--; and/or
R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are independently selected
from the group consisting of (a) hydrogen; (b) alkyl; (c)
cycloalkyl; (d) cycloalkylalkyl; (e) hydroxyalkyl; (f)
hydroxylalkoxyalkyl; (g) aryl substituted by R.sup.6, R.sup.7 and
R.sup.8 ; (h) arylalkyl substituted by R.sup.6, R.sup.7 and R.sup.8
; (i) alkoxycarbonyl; (j) alkoxycarbonylalkyl; (k) carboxyalkyl;
(1) aminoalkyl; (m) thiolalkyl; (n) heterocyclic; (o)
(heterocyclic)alkyl; (p) (heterocyclic)alkylaminoalkyl; (q) acyl;
(r) N-mono- or N,N-dialkylaminoalkyl; (s) N-mono- or
N,N-dialkylcarboxamidoalkyl; (t) N-mono- or
N,N-diarylcarboxamidoalkyl; and (u) formyl.
Also preferred are those compounds in which X in the heterocyclic
ring of formula (II) is selected from the group consisting of
--N(R.sup.1)-- and --C(R.sup.2)(R.sup.2')--, and the total of m and
n is zero, one or two (that is, where the heterocycle is a 5- to
7-membered ring).
Representative of the compounds of the present invention are those
which are demonstrated in Examples 5, 7, 9, 11-22, 27, 28, 31, 38,
39, 44, 58, 61, 62, 67, 76 and 105-111, below. The most preferred
of these compounds, and that contemplated as the best mode thereof,
is the compound described in Example 17 hereof.
As used throughout this specification and in the appended claims,
the following terms have the meanings specified:
The term "acyl" as used herein refers to an aryl or alkyl group, as
defined below, appended to a carbonyl group including, but not
limited to, acetyl, pivaloyl, benzoyl and the like.
The term "alkenyl" as used herein refers to straight or branched
chain groups of 2 to 12 carbon atoms containing a carbon-carbon
double bond including, but not limited to ethenyl, 1-propenyl,
2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the
like.
The terms "alkoxy" as used herein refer to a loweralkyl group, as
defined below, attached to the remainder of the molecule through an
oxygen atom including, but not limited to, methoxy, ethoxy,
isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy and the
like.
The terms "alkoxyalkyl" as used herein refers to an alkoxy group,
as defined above, appended to an alkyl group including, but not
limited to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl,
i-propyloxymethyl, n-butoxyethyl and the like.
The term "alkoxycarbonyl" as used herein refers to an alkoxy group,
as defined above, attached via a carbonyl group including, but not
limited to, methyloxycarbonyl, ethyloxycarbonyl,
tert-butyloxycarbonyl, cyclohexyloxycarbonyl and the like.
The term "alkoxycarbonylalkyl" as used herein refers to an
alkoxycarbonyl group, as defined above, attached via an alkyl group
including, but not limited to, methyloxycarbonylmethyl,
ethyloxycarbonylethyl, tert-butyloxycarbonylmethyl,
cyclohexyloxycarbonylmethyl and the like.
The term "alkyl" as used herein refers to a monovalent straight
chain or branched chain group of 1 to 12 carbon atoms including,
but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl,
sec-butyl, isobutyl, tert-butyl and the like.
The terms "alkylamino" and "loweralkylamino" as used herein refer
to a group having the structure --NH-(loweralkyl), where the
loweralkyl portion is as defined below. Alkylamino and
loweralkylamino groups include, for example, methylamino,
ethylamino, isopropylamino and the like.
The term "alkylsulfonyl" as used herein refers to an alkyl group,
as defined above, attached via a sulfur dioxide diradical
including, but not limited to, methanesulfonyl, camphorsulfonyl and
the like.
The terms "alkylthioether", "thioalkoxy" and "thioloweralkoxy" as
used herein refer to a loweralkyl group, as previously defined,
attached via a sulfur atom including, but not limited to,
thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy,
sec-thiobutoxy, isothiobutoxy, tert-thiobutoxy and the like.
The term "alkynyl" as used herein refers to straight or branched
chain groups of 2 to 12 carbon atoms containing a carbon-carbon
triple bond including, but not limited to acetylenyl, propargyl and
the like.
The term "amidoalkyl" as used herein refers to a group having the
structure --N(R.sup.401)C(O)R.sup.402 appended to a loweralkyl
group, as previously defined. The groups R.sup.401 and R.sup.402
are independently selected from hydrogen, lower alkyl, aryl,
arylalkyl, and halosubstituted alkyl. Alternatively, R.sup.401 and
R.sup.402, taken together, may be --(CH.sub.2).sub.aa -- where aa
is an integer of from two to six.
The term "aminoalkyl" as used herein refers to a group having the
structure --NR.sup.403 R.sup.404 appended to a loweralkyl group, as
previously defined. The groups R.sup.403 and R.sup.404 are
independently selected from hydrogen, lower alkyl, aryl and
arylalkyl. Alteratively, R.sup.403 and R.sup.404, taken together,
may be --(CH.sub.2).sub.bb -- where bb is an integer of from two to
six.
The terms "aryl" as used herein refers to carbocyclic aromatic
groups including, but not limited to, phenyl, 1- or 2-naphthyl,
fluorenyl, (1, 2)-dihydronaphthyl, (1,2,3,4)-tetrahydronaphthyl,
indenyl, indanyl and the like.
The terms "arylalkoxy" and "arylalkylether" as used herein refer to
an arylalkyl group, as defined below, attached to the parent
molecular moiety through an oxygen atom. Arylalkoxy includes, but
is not limited to, benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy
and the like.
The term "arylalkoxycarbonyl" as used herein refers to an
arylalkoxy group, as defined above, attached via a carbonyl group
including, but not limited to, benzyloxycarbonyl,
9-fluorenylmethyloxycarbonyl and the like.
The term "arylalkyl" as used herein refers to an aryl group, as
previously defined, appended to an alkyl group including, but not
limited to, benzyl, 1- and 2-naphthylmethyl, halobenzyl,
alkoxybenzyl, hydroxybenzyl, aminobenzyl, nitrobenzyl,
guanidinobenzyl, fluorenylmethyl, phenylmethyl(benzyl),
1-phenylethyl, 2-phenylethyl, 1-naphthylethyl and the like.
The terms "arylether" and "aryloxy" as used herein refer to an aryl
group, as previously defined, attached to the parent molecular
moiety through an oxygen atom. Aryloxy and arylether include, but
are not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy and the
like.
The term "aryloxycarbonyl" as used herein refers to an aryloxy
group, as defined above, attached via a carbonyl group including,
but not limited to, phenyloxycarbonyl.
The term "aryloxycarbonylamino" as used herein refers to an
aryloxycarbonyl group, as defined above, appended to an amino group
including, but not limited to, phenyloxycarbonylamino.
The term "arylsulfonyl" as used herein refers to an aryl group, as
defined above, attached via a sulfur dioxide diradical including,
but not limited to p-toluenesulfonyl, benzenesulfonyl and the
like.
The terms "arylthioether" and "thioaryloxy" as used herein refer to
an aryl group, as defined above, attached via a sulfur atom.
The term "carboxamido" as used herein refers to an amino group
attached via a carbonyl group and having the formula
--C(O)NH.sub.2.
The term "carboxyalkyl" as used herein refers to a carboxyl group,
--CO.sub.2 H, appended to a loweralkyl group, as previously
defined.
The term "cycloalkenyl" as used herein refers to a cyclic group of
5 to 10 carbon atoms possessing one or more carbon-carbon double
bonds including, but not limited to, cyclopentenyl, cyclohexenyl
and the like, in which the point of attachment can occur at any
available valency on the carbocylic ring.
The term "cycloalkyl" as used herein refers to a cyclic group of 3
to 8 carbon atoms including, but not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term "cycloalkylalkenyl" as used herein refers to a cycloalkyl
group, as defined above, appended to an alkenyl group, as defined
above.
The term "cycloalkylalkyl" as used herein refers to a cycloallcyl
group appended to a lower alkyl group including, but not limited
to, cyclohexylmethyl and cyclohexylethyl.
The term "cycloalkylalkynyl" as used herein refers to cycloalkyl,
as defined above, appended to an alkynyl group, as defined
above.
The term "guanidinoalkyl" as used herein refers to a group of the
structure --N(R.sup.405)C(.dbd.NR.sup.406)NHR.sup.407 appended to a
loweralkyl group, as previously defined. R.sup.405, R.sup.406 and
R.sup.407 are independently selected from hydrogen, lower alkyl,
heterocyclic, aminoalkyl and aryl. Alternatively, R.sup.406 and
R.sup.407, taken together, may be --(CH.sub.2).sub.cc -- where cc
is an integer of from two to six.
The terms "halo" and "halogen" as used herein refer to an atom
selected from fluorine, chlorine, bromine and iodine.
The terms "haloalkyl" as used herein refer to halogen appended to
an alkyl group, as previously defined.
The term "heterocyclic" as used herein, except where otherwise
specified, refers to any aromatic or non-aromatic 5-, 6- or
7-membered ring or a bi- or tri-cyclic group comprising fused
six-membered rings having between one and three heteroatoms
independently selected from oxygen, sulfur and nitrogen, wherein
(i) each 5-membered ring has 0 to 2 double bonds and each
6-membered ting has 0 to 3 double bonds, (ii) the nitrogen and
sulfur heteroatoms as well as the carbon atoms may optionally be
oxidized by unsaturation and/or substitution by hydroxy, thiol, oxo
or thiooxo, (iii) the nitrogen heteroatom may optionally be
quaternized, (iv) any of the above heterocyclic rings may be fused
to a benzene ring. Representative heterocycles include, but are not
limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl,
pyrazolidinyl, cytosinyl, thiocytosinyl, imidazolyl, imidazolinyl,
imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl,
pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl,
oxazoyl, oxazolidinyl, thiouracilyl, isoxazolyl, isoxazolidinyl,
morpholinyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl,
thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,
isoquinolinyl, thyminyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, furyl, thienyl and benzothienyl.
The term "(heterocyclic)alkyl" as used herein refers to a
heterocyclic group appended to an alkyl group, as previously
defined.
The term "(heterocyclic)alkylaminoalkyl" as used herein refers to a
(heterocyclic)alkyl group appended to an aminoalkyl group, as
previously defined.
The term "(heterocyclic)alkylether" as used herein refers to a
(heterocyclic)alkyl moiety, as defined above, attached via an
oxygen atom.
The term "(heterocyclic)alkenyl" as used herein refers to a
heterocyclic group appended to an alkenyl group, as previously
defined.
The term "(heterocyclic)alkylthioether" as used herein refers to a
(heterocyclic)alkyl moiety, as defined above, attached via a sulfur
atom.
The term "(heterocyclic)alkynyl" as used herein refers to a
heterocyclic group appended to an alkynyl group, as previously
defined.
The term "(heterocyclic)ether" as used herein refers to a
heterocyclic moiety, as defined above, attached via an oxygen
atom.
The term "(heterocyclic)thioether" as used herein refers to a
heterocyclic moiety, as defined above, attached via a sulfur
atom.
The terms "hydroxyalkyl" as used herein refer to -OH appended to a
loweralkyl group, as defined below.
The terms "hydroxyalkyloxyalkyl" as used herein refer to --OH
appended to an alkyloxyalkyl group, as defined above.
The term "hydroxy-protecting group" as used herein refers to those
groups which are known in the an to protect a hydroxyl group
against undesirable reaction during synthetic procedures and to be
selectively removable including, but not limited to,
dimethylthexylsilyl, trisubstituted silyl such as
tri(lower)alkylsilyl (e.g. trimethylsilyl, triethylsilyl,
tributylsilyl, tri-i-propylsilyl, tert-butyl-dimethylsilyl,
tri-tert-butylsilyl, triphenylmethyl-dimethylsilyl, etc.); lower
alkyldiarylsilyl (e.g. methyl-diphenylsilyl, ethyl-diphenylsilyl,
propyl-diphenylsilyl, tert-butyl-diphenylsilyl, etc.), and the
like; triarysilyl (e.g. triphenylsilyl, tri-p-xylylsilyl, etc.);
triarylalkylsilyl (e.g. tribenzylsilyl, etc.), acyl substituted
with an aromatic group and the like. Other classes of
hydroxy-protecting group which may be useful include, but are not
limited to, chlorocarbonate analogues such as
trimethylsilylethoxycarbonyl, methylthiomethoxyethoxycarbonyl or
benzenesulfonylethoxycarbonyl; trimethylsilylethoxymethyl, and the
like,
The term "loweralkyl" as used herein refers to an alkyl group, as
defined above, of 1 to 8 carbon atoms.
The terms "monoalkylamino" and "dialkylamino" refer respectively to
one and two alkyl or cycloalkyl groups, as defined above, appended
to an amino group including, but not limited to, methylamino,
isopropylamino, cyclohexylamino, dimethylamino,
N,N-methylisopropylamino; bis-(cyclohexyl)amino and the like.
The term "N-alkylcarboxamido" as used herein refers to an
alkylamino group, as defined above, attached via a carbonyl group
and having the formula HN(alkyl)C(O)--.
The term "N-arylcarboxamido" as used herein refers to an arylamino
group, as defined above, attached via a carbonyl group and having
the formula HN(aryl)C(O)--.
The term "N,N-dialkylcarboxamido" as used herein refers to an amino
group substituted with two alkyl groups, as defined above, wherein
the two alkyl groups need not be identical, attached via a carbonyl
group and having the formula N(alkyl)(alkyl')C(O)--.
The term "N,N-diarylcarboxamido" as used herein refers to an amino
group substituted with two aryl groups, as defined above, wherein
the two aryl groups need not be identical, attached via a carbonyl
group and having the formula N(aryl)(aryl')C(O)--.
The term "N-alkylcarboxamidoalkyl" as used herein refers to an
alkylcarboxamido group, as defined above, attached via an alkyl
group and having the formula HN(alkyl)C(O)-alkyl--.
The term "N-arylcarboxamidoalkyl" as used herein refers to an
arylcarboxamido group, as defined above, attached via an alkyl
group and having the formula HN(aryl)C(O)-alkyl--.
The term "N,N-dialkylcarboxamidoalkyl" as used herein refers to an
amino group substituted with two alkyl groups, as defined above,
wherein the two alkyl groups need not be identical, attached via a
carbonyl group and having the formula
N(alkyl)(alkyl')C(O)-alkyl--.
The term "N,N-diarylcarboxamido" as used herein refers to an amino
group substituted with two aryl groups, as defined above, wherein
the two aryl groups need not be identical, attached via a carbonyl
group and having the formula N(aryl)(aryl')C(O)-alkyl--.
The term "oxo" as used herein refers to an oxygen atom forming a
carbonyl group.
The term "polyhydroxyalkyl" as used herein refers to two or more
hydroxyl groups appended to an alkyl group, as defined above.
The term "protected formyl group" as used herein refers to those
groups which are known in the an to protect a formyl group against
undesirable reaction during synthetic procedures and to be
selectively removable including, but not limited to, dimethyl
acetal, diethyl acetal, bis(2,2,2-trichloroethyl) acetals, Dibenzyl
acetal, 1,3-dioxane, 5-methylene1,3-dioxane,
5,5-dibromo-1,3-dioxane, 0-methyl--S-2-(methylthio)ethyl acetal,
1,3-oxathiolanes and the like.
The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy
group, as defined above, appended to a loweralkyl group.
The term "thioalkyl" as used herein refers to an alkyl group, as
defined above, attached via a sulfur atom.
The term "thiooxo" as used herein refers to a sulfur atom forming a
thiocarbonyl group.
The term "pharmaceutically acceptable salts, esters, amides and
prodrugs" as used herein refers to those carboxylate salts, amino
acid addition salts, esters, amides and prodrugs of the compounds
of the present invention which are, within the scope of sound
medical judgement, suitable for use in contact with with the
tissues of humans and lower animals with undue toxicity,
irritation, allergic response, and the like, commensurate with a
reasonable benefit/risk ratio, and effective for their intended
use, as well as the zwitterionic forms, where possible, of the
compounds of the invention. The term "salts" refers to the
relatively non-toxic, inorganic and organic acid addition salts of
compounds of the present invention. These salts can be prepared in
situ during the final isolation and purification of the compounds
or by separately reacting the purified compound in its free base
form with a suitable organic or inorganic acid and isolating the
salt thus formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,
oxalate, valerate, oleate, palmitate, stearate, laurate, borate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate, mesylate, glucoheptonate,
lactiobionate and laurylsulphonate salts and the like. These may
include cations based on the alkali and alkaline earth metals, such
as sodium, lithium, potassium, calcium, magnesium and the like, as
well as nontoxic ammonium, quaternary ammonium and amine cations
including, but not limited to, ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, ethylamine and the like. (See, for example S. M.
Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19
(1977) which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non-toxic esters of the
compounds of this invention include C.sub.1 -to-C.sub.6 alkyl
esters wherein the alkyl group is a straight or branched chain.
Acceptable esters also include C.sub.5 -to-C.sub.7 cycloalkyl
esters as well as arylalkyl esters such as, but not limited to
benzyl. C.sub.1 -to-C.sub.4 alkyl esters are preferred. Esters of
the compounds of the present invention may be prepared according to
conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the
compounds of this invention include amides derived from ammonia,
primary C.sub.1 -to-C.sub.6 alkyl amines and secondary C.sub.1
-to-C.sub.6 dialkyl amines wherein the alkyl groups are straight or
branched chain. In the case of secondary amines the amine may also
be in the form of a 5 or 6 membered heterocycle containing one
nitrogen atom. Amides derived from ammonia, C.sub.1 -to-C.sub.3
alkyl primary amides and C.sub.1 -to-C.sub.2 dialkyl secondary
amides are preferred. Amides of the compounds of the invention may
be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed
in vivo to yield the parent compound of the above formula, for
example by hydrolysis in blood. A thorough discussion is provided
in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems",
Vol 14, of the A.C.S. Symposium Series, and in Bioreversible
Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987, both of which
are incorporated herein by reference.
Where appropriate, prodrugs of Derivatives of compounds of the
present invention may be prepared by any suitable method. For those
compounds in which the prodrug moiety is an amino acid or peptide
functionality, the condensation of the amino group with amino acids
and peptides may be effected in accordance with conventional
condensation methods such as the azide method, the mixed acid
anhydride method, the DCC (dicyclohexylcarbodiimede) method, the
active ester method (p-nitrophenyl ester method, N-hydroxysuccinic
acid imide ester method, cyanomethyl ester method and the like),
the Woodward reagent K method, the DCC-HOBT
(1-hydroxy-benzotriazole) method and the like. Classical methods
for amino acid condensation reactions are described in "Peptide
Synthesis" Second Edition, M. Bodansky, Y. S. Klausher and M. A.
Ondetti (1976).
As in conventional peptide sysnthesis, branched chain amino and
carboxyl groups at alpha and omega positions in amino acids may be
protected and deprotected if necessary. The protecting groups for
amino groups which can be used involve, for example,
benzyloxycarbonyl (Z), o-chlorobenzyloxycarbonyl ((2-Cl)Z)),
p-nitrobenzyloxycarbonyl (Z(NO.sub.2)), p-methoxybenzyloxycarbonyl
(Z(OMe)), t-amyloxycarbonyl (Aoc), isobomealoxycarbonyl,
adamantyloxycarbonyl (Adoc), 2-(4-biphenyl)-2-propyloxy carbonyl
(Bpoc), 9-fluorenyl-methoxycarbonyl (Fmoc), methylsulfonylethoxy
carbonyl (Msc), trifluoroacetyl, phthalyl, formyl,
2-nitrophenylsulfonyl (Nps), diphenylphosphinothioyl (Ppt) and
dimethylphosphino-thioyl (Mpt).
The examples for protecting groups for carboxyl groups involve, for
example, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester
(OBzlNO2), t-butyl ester (OtBu), 4-pyridylmethyl ester (OPic) and
the like.
In the course of the synthesis of certain of the compounds of the
present invention, specific amino acids having functional groups
other than amino and carboxyl groups in the branched chain such as
arginine, cysteine, serine and the like may be protected, if
necessary, with suitable protecting groups. It is preferable that,
for example, the guanidino group (NG) in arginine may be protected
with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z),
adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl,
4-methoxy-2,6-dimethylbenzenesulfonyl (Mts) and the like; the thiol
group in cysteine may be protected with benzyl, p-methoxybenzyl,
triphenylmethyl, acetamidomethyl, ethylcarbamyl, 4-methylbenzyl
(4-MeBzl), 2,4,6-trimethylbenzyl (Tmb) and the like; and the
hydroxy group in serine may be protected with benzyl (Bzl),
t-butyl, acetyl, tetrahydropyranyl (THP) and the like.
Numerous asymmetric centers may exist in the compounds of the
present invention. Except where otherwise noted, the present
invention contemplates the various stereoisomers and mixtures
thereof. Accordingly, whenever a bond is represented by a wavy
line, it is intended that both steric orientations are
intended.
It should also be noted that certain variable elements of the
structural formulae herein, such as the radicals R.sup.11 and
R.sup.12 or the integers m, s and t, may appear more than once in a
particular formula. In such instances, it is intended that, within
a single formula, the values of these variables may be the same or
different at each occurrence.
The compounds of the invention, including but not limited to those
specified in the examples, possess immunomodulatory activity in
animals. As immunosuppressants, the compounds of the present
invention may be useful for the treatment and prevention of immune
mediated diseases such as the resistance by transplantation of
organs or tissue such as heart, kidney, liver, medulla ossium,
skin, cornea, lung, pancreas, intestinum tenue, limb, muscle,
nervus, duodenum, small-bowel, pancreatic-islet-cell, etc.;
graft-versus-host diseases brought about by medulla ossium
transplantation; autoimmune diseases such as rheumatoid arthritis,
systemic lupus erythematosus, Hashimoto's thyroidiris, multiple
sclerosis, myasthenia gravis, type I diabetes uveitis, allergic
encephalomyelitis, glomerulonephritis, and the like; and further
infectious diseases caused by pathogenic microorganisms. Further
uses may include the treatment and prophylaxis of inflammatory and
hyperproliferative skin diseases and cutaneous manifestations of
immunologically-mediated illnesses, such as psoriasis, atopical
dermatitis, contact dermatitis and further eczematous dermatitises,
seborrhoeis dermatitis, Lichen planus, Pemphigus, bullous
pemphigoid, Epidermolysis bullosa, urticaria, angioedemas,
vasculitides, erythemas, cutaneous eosinophilias, Lupus
erythematosus, acne and Alopecia arcata; various eye diseases
(autoimmune and otherwise) such as keratoconjunctivitis, vemal
conjunctivitis, uveitis associated with Behcet's disease,
keratitis, herpetic keratitis, conical cornea, dystrophia
epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's
ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada
syndrome, sarcoidosis, etc.; reversible obstructive airway disease,
which includes condition such as asthma (for example, bronchial
asthma, allergic asthma, intrinsic asthma, extrinsic asthma and
dust asthma), particularly chronic or inveterate asthma (for
example, late asthma and airway hyper-responsiveness), bronchitis
and the like; intimation of mucosa and blood vessels such as
gastric ulcers, vascular damage caused by ischemic diseases and
thrombosis, ischemic bowel diseases, inflammatory bowel diseases,
necrotizing enterocolitis, intestinal lesions associated with
thermal bums and leukotriene B.sub.4 -mediated diseases; intestinal
inflammations/allergies such as Coeliac diseases, proctitis,
eosinophilic gastroenteritis, mastocytosis, Crohn's disease and
ulcerative colitis; food-related allergic diseases which have
symptomatic manifestation remote from the gastrointestinal tract
(e.g. migraine, rhinitis and eczema); renal diseases such as
interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic
syndrome and diabetic nephropathy; nervous diseases such as
multiple myositis, Guillain-Barre syndrome, Meniere's disease,
polyneuritis, multiple neuritis, mononeuritis and radiculopathy;
endocrine diseases such as hyperthyroidism and Basedow's disease;
hematic diseases such as pure red cell aplasia, aplastic anemia,
hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune
hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic
anemia and anerythroplasia; bone diseases such as osteoporosis;
respiratory diseases such as sarcoidosis, fibroid lung and
idiopathic interstitial pneumonia; skin disease such as
dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris,
photoallergic sensitivity and cutaneous T cell lymphoma;
circulatory diseases such as arteriosclerosis, atherosclerosis,
aortitis syndrome, polyaneritis nodosa and myocardosis; collagen
diseases such as scleroderma, Wegener's granuloma and Sjogren's
syndrome; adiposis; eosinophilic fasciitis; periodontal disease
such as lesions of gingiva, periodontium, alveolar bone and
substantia ossea dentis; nephrotic syndrome such as
glomerulonephritis; male pattern alopecia or alopecia senilis by
preventing epilation or providing hair germination and/or promoting
hair generation and hair growth; muscular dystrophy; Pyoderma and
Sezary's syndrome; Addison's disease; active oxygen-mediated
diseases, as for example organ injury such as ischemia-reperfusion
injury of organs (such as heart, liver, kidney and digestive tract)
which occurs upon preservation, transplantation or ischemic disease
(for example, thrombosis and cardiac infraction): intestinal
diseases such as endotoxin-shock, pseudomembranous colitis and
colitis caused by drug or radiation; renal diseases such as
ischemic acute renal insufficiency and chronic renal insufficiency;
pulmonary diseases such as toxinosis caused by lung-oxygen or drug
(for example, paracort and bleomycins), lung cancer and pulmonary
emphysema; ocular diseases such as cataracta, siderosis, retinitis,
pigmentosa, senile macular degeneration, vitreal scarring and
corneal alkali bum; dermatitis such as erythema multiforme, linear
IgA ballous dermatitis and cement dermatitis; and others such as
gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by
environmental pollution (for example, air pollution), aging,
carcinogenis, metastasis of carcinoma and hypobaropathy; disease
caused by histamine or leukotriene-C.sub.4 release; Behcet's
disease such as intestinal-, vasculo- or neuro-Behcet's disease,
and also Behcet's which affects the oral cavity, skin, eye, vulva,
articulation, epididymis, lung, kidney and so on. Furthermore, the
compounds of the invention are useful for the treatment and
prevention of hepatic disease such as immunogenic diseases (for
example, chronic autoimmune liver diseases such as the group
consisting of autoimmune hepatitis, primary biliary cirrhosis and
sclerosing cholangitis), partial liver resection, acute liver
necrosis (e.g. necrosis caused by toxin, viral hepatitis, shock or
anoxia), B-virus hepatitis, non-A/non-B hepatitis, cirrhosis (such
as alcoholic cirrhosis) and hepatic failure such as fulminant
hepatic failure, late-onset hepatic failure and "acute-on-chronic"
liver failure (acute liver failure on chronic liver diseases), and
moreover are useful for various diseases because of their useful
activity such as augmention of chemotherapeutic effect, preventing
or treating activity of cytomegalovirus infection, particularly
HCMV infection, anti-inflammatory activity, and so on.
Additionally, some compounds appear to possess FK-506 antagonistic
properties. The compounds of the present invention may thus be used
in the treatment of immunodepression or a disorder involving
immunodepression. Examples of disorders involving immunodepression
include AIDS, cancer, senile dementia, trauma (including wound
healing, surgery and shock) chronic bacterial infection, and
certain central nervous system disorders. The immunodepression to
be treated may be caused by an overdose of an immunosuppressive
macrocyclic compound, for example derivatives of 12-(2-cyclohexyl-
1-methylvinyl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0.
sup.4,9 ]octacos-18-ene such as FK-506, or rapamycin. Overdosing of
such medicants by patients is quite common upon their realizing
that they have forgotten to take their medication at the prescribed
time and can lead to serious side effects.
The compounds of the present invention may also find utility in the
chemosensitization of drug resistant target cells. Cyclosporin A
and FK-506 are known to be effective modulators of P-glycoprotein,
a compound which binds to and inhibits the action of anti-cancer
drugs; by inhibiting P-glycoprotein, they are capable of increasing
the sensitivity of multidrug resistant (MDR) cells to
chemotherapeutic agents. It is believed that the compounds of the
invention may likewise be effective at overcoming resistance
expressed to clinically useful anti-tumour drugs such as
5-fluorouracil, cisplatin, methotrexate, vincristine, vinblastine
and adriamycin, colchicine and vincristine.
A further situation in which the compounds of the present invention
may be used to treat immunosuppression is in vaccination. It is
sometimes found that the antigen introduced into the body for the
acquisition of immunity from disease acts as an immunosuppressive
agent, and so antibodies are not produced by the body and immunity
is not acquired. By introducing a compound of the invention into
the body (as in a vaccine), the undesired immunosuppression may be
overcome and immunity acquired.
Aqueous liquid compositions of the present invention may be
particularly useful for the treatment and prevention of various
diseases of the eye such as autoimmune diseases (including, for
example, conical cornea, keratitis, dysophia epithelialis corneae,
leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and
rejection of corneal transplantation.
When used in the above or other treatments, a therapeutically
effective amount of one of the compounds of the present invention
may be employed in pure form or, where such forms exist, in
pharmaceutically acceptable salt, ester or prodrug form.
Alternatively, the compound may be administered as pharmaceutical
compositions containing the compound of interest in combination
with one or more pharmaceutically acceptable excipients. By a
"therapeutically effective amount" of the compound of the invention
is meant a sufficient amount of the compound to treat
gastrointestinal disorders, at a reasonable benefit/risk ratio
applicable to any medical treatment. It will be understood,
however, that the total daily usage of the compounds and
compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgement.
The specific therapeutically effective dose level for any
particular patient will depend upon a variety of factors including
the disorder being treated and the severity of the disorder;
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well known in the medical arts. For example, it is well
within the skill of the art to start doses of the compound at
levels lower than required for to achieve the desired therapeutic
effect and to gradually increase the dosage until the desired
effect is achieved.
The total daily dose of the compounds of this invention
administered to a human or lower animal may range from about 0.001
to about 3 mg/kg/day. For purposes of oral administration, more
preferable doses may be in the range of from about 0.005 to about
1.5 mg/kg/day. If desired, the effective daily dose may be divided
into multiple doses for purposes of administration; consequently,
single dose compositions may contain such amounts or submultiples
thereof to make up the daily dose.
The pharmaceutical compositions of the present invention comprise a
compound of the invention and a pharmaceutically acceptable carder
or excipient, which may be administered orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, drops or transdermal patch),
bucally, or as an oral or nasal spray. By "pharmaceutically
acceptable carder" is meant a non-toxic solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. The term "parenteral" as used herein refers to modes of
administration which include intravenous, intramuscular,
intraperitoneal, intrasternal, subcutaneous and intraarticular
injection and infusion.
Pharmaceutical compositions of this invention for parenteral
injection comprise pharmaceutically acceptable sterile aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions as well
as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and nonaqueous carders, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), carboxymethylcellulose
and suitable mixtures thereof, vegetable oils (such as olive oil),
and injectable organic esters such as ethyl oleate. Proper fluidity
can be maintained, for example, by the use of coating materials
such as lecithin, by the maintenance of the required particle size
in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative,
wetting agents, emulsifying agents, and dispersing agents.
Prevention of the action of microorganisms may be ensured by the
inclusion of various antibacterial and antifungal agents, for
example, paraben, chlorobutanol, phenol sorbic acid, and the like.
It may also be desirable to include isotonic agents such as sugars,
sodium chloride, and the like, Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices
of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides) Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
The injectable formulations can be sterilized, for example, by
filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric
coatings and other coatings well known in the pharmaceutical
formulating art. They may optionally contain opacifying agents and
can also be of a composition that they release the active
ingredient(s) only, or preferentially, in a certain part of the
intestinal tract, optionally, in a delayed manner. Examples of
embedding compositions which can be used include polymeric
substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned
excipients.
Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
Besides inert diluents, the oral compositions can also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain
suspending agents as, for example, ethoxylated isostearyl alcohols,
polyoxyethylene sorbitol and sorbitan esters, microcrystalline
cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, and mixtures thereof.
Topical administration includes administration to the skin or
mucosa, including surfaces of the lung and eye. Compositions for
topical administration, including those for inhalation, may be
prepared as a dry powder which may be pressurized or
non-pressurized. In non-pressurized powder compositions, the active
ingredient in finely divided form may be used in admixture with a
larger-sized pharmaceutically acceptable inert carder comprising
particles having a size, for example, of up to 100 micrometers in
diameter. Suitable inert carders include sugars such as lactose.
Desirably, at least 95% by weight of the particles of the active
ingredient have an effective particle size in the range of 0.01 to
10 micrometers.
Alternatively, the composition may be pressurized and contain a
compressed gas, such as nitrogen or a liquified gas propellant. The
liquified propellant medium and indeed the total composition is
preferably such that the active ingredient does not dissolve
therein to any substantial extent. The pressurized composition may
also contain a surface active agent. The surface active agent may
be a liquid or solid non-ionic surface active agent or may be a
solid anionic surface active agent. It is preferred to use the
solid anionic surface active agent in the form of a sodium
salt.
A further form of topical administration is to the eye, as for the
treatment of immune-mediated conditions of the eye such as
automimmue diseases, allergic or inflammatory conditions, and
corneal transplants. The compound of the invention is delivered in
a pharmaceutically acceptable ophthalmic vehicle, such that the
compound is maintained in contact with the ocular surface for a
sufficient time period to allow the compound to penetrate the
corneal and internal regions of the eye, as for example the
anterior chamber, posterior chamber, vitreous body, aqueous humor,
vitreous humor, cornea, iris/cilary, lens, choroid/retina and
sclera. The pharmaceutically acceptable ophthalmic vehicle may, for
example, be an ointment, vegetable oil or an encapsulating
material.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this
invention with suitable non-irritating excipients or carriers such
as cocoa butter, polyethylene glycol or a suppository wax which are
solid at room temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity and release the
active compound.
Compounds of the present invention can also be administered in the
form of liposomes. As is known in the art, liposomes are generally
derived from phospholipids or other lipid substances. Liposomes are
formed by mono- or multi-lamellar hydrated liquid crystals that are
dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes can
be used. The present compositions in liposome form can contain, in
addition to a compound of the present invention, stabilizers,
preservatives, excipients, and the like. The preferred lipids are
the phospholipids and the phosphatidyl cholines (lecithins), both
natural and synthetic. Methods to form liposomes are known in the
art. See, for example, Prescott, Ed., Methods in Cell Biology,
Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et
seq.
The compounds of the invention may be prepared using one or more of
the processes which follow. The starting materials for use in these
processes are preferably one of the macrofides isolated from
culture media obtained in accordance with known methods by
fermentation of microorganisms of the genus Streptomyces, which are
disclosed in European Patent Application No. 0184162. Samples are
available from the Fermentation Research Institute, Tsukuba,
Ibaraki 305, Japan under the provisions of the Budapest Treaty,
under deposit No. FERM BP-927. This strain has been redeposited on
Apr. 27, 1989 with the Agricultural Research Culture Collection
International Depository, Peoria, Ill. 61604, USA under the
provisions of the Budapest Treaty, under deposit No. NRRL 18488.
The macrolide FR-900520 (European Patent Application 0184162), also
known as ascomycin, may be prepared in accordance to the published
methods of (i) H. Hatanaka, M. Iwami, T. Kino, T. Goto and M.
Okuhara, FR-900520 and FR-900523, Novel immunosuppressants isolated
from A streptomyces. I. Taxonomy of the producing strain. J.
Antibiot., 1988. XLI(11), 1586-1591; (ii) H. Hatanaka, T. Kino, S.
Miyata, N. Inamura, A. Kuroda, T. Goto, H. Tanaka and M. Okuhara,
FR-900520 and FR-900523, Novel immunosuppressants isolated from A
streptomyces. II. Fermentation, isolation and physico-chemical and
biological characteristics. J. Antiblot., 1988. XLI(11), 1592-160
1; (iii) T. Arai, Y. Koyama, T. Suenaga and H. Honda, Ascomycin, An
Antifungal Antibiotic. J. Antibiot., 1962. 15(231-2); and (iv) T.
Arai in U.S. Pat. No. 3,244,592. One or more of the processes
discussed below may be then employed to produce the desired
compound of the invention.
Such processes comprise:
(a) producing a compound of formula I, which contains bis(CH--OR)
groups, in a corresponding compound wherein R is a protecting
group.
(b) producing a compound of formula I, which contains a mono(CH-OR)
group, by selective deprotection in a corresponding compound
wherein R is a protecting group.
(c) producing a compound of formula I, which contains a CH--OR
group, by selective activation of a selected CH--OH group in a
corresponding compound wherein --OR is a leaving group which is
easily displaced by nucleophilic attack.
(d) producing a compound of formula I, which contains a
CH--R.sup.100 group, by selective displacement of a selected CH--OR
group in a corresponding compound wherein --R.sup.100 is a
nucleophile.
(e) producing a compound of formula I, which contains a CH--OH
group, by selective and final deprotection in a corresponding
compound.
In process (a), suitable protecting groups for hydroxyl include
those groups well known in the art such as dimethylthexylsilyl,
trisubstituted silyl such as tri(lower)alkylsilyl (e.g.
trimethylsilyl, triethylsilyl, tributylsilyl, tri-i-propylsilyl,
tert-butyl-dimethylsilyl, tri-tert-butylsilyl,
triphenylmethyl-dimethylsilyl, etc.); lower alkyldiarylsilyl (e.g.
methyldiphenylsilyl, ethyl-diphenylsilyl, propyl-diphenylsilyl,
tert-butyl-diphenylsilyl, etc.), and the like; triarysilyl (e.g.
triphenylsilyl, tri-p-xylylsilyl, etc.); triarylalkylsilyl (e.g.
tribenzylsilyl, etc.), and the like, in which the preferred one may
be tri(C.sub.1 -to-C.sub.4)alkylsilyl and C.sub.1 -to-C.sub.4
alkyldiphenylsilyl, and the most preferred one may be
tert-butyldimethylsilyl;
Suitable o-silylations may be carried out using a wide variety of
organosilicon reagents such as, but not limited to
tert-butyldimethylsilyl chloride,
N-(tert-butyldimethylsilyl)N-methyltrifiuoroacetamide (Mawbinney,
T., and Madison, M. A. J. Org. Chem., 1982, 47, 3336),
tert-butylchlorodiphenylsilane (Hanessian, S. and Lavalice, P Can.
J. Chem., 1975, 63, 2975), tert-butyldimethylsilyl
trifluoromethanesulfonate (Mander, L. N. and Sethi, S. P.
Tetrahedron Lett., 1984, 25, 5953), dimethylthexylsilyl chloride or
dimethylthexylsilyl trifluoromethanesulfonate (Wetter, H. and
Oertle, K. Tetrahedron Lett., 1985, 26, 5515),
1-(tert-butyldimethylsilyl)-imidazole and the like.
Carbonate hydroxy-protecting groups may be introduced using a wide
variety of a haloformates such as methy, ethyl,
2,2,2-trichloroethyl, isobutyl, vinyl, allyl,
2-(trimethylsilyl)ethyl, 2-(benzenesulfonyl)ethyl,
2-(trimethylsilyl)ethoxy methyl, benzyl and substituted benzyl
chloroformates, where benzyl substituents include p2methoxy,
3,4-dimethoxy and p-nitro, in the presence of tertiary base such as
pyridine, triethylamine, imidazole, diisopropylethylamine and the
like. (Tetrahedron Lett., 1980, 21, 3343; ibid., 1981, 22, 3667;
ibid. 1981, 22,969; ibid. 1981, 22, 1933.)
The reaction may be carried out in a solvent which does not
adversely affect the reaction (e.g., diethylether, dichloromethane,
tetrahydrofuran, chloroform or N,N-dimethylformamide or a mixture
thereof). The reaction may require cooling or heating, depending on
the activation method chosen. Further, the reaction is preferably
conducted in the presence of an organic or inorganic base such as
an alkaline earth metal (e.g. calcium, etc.), alkali metal hydride
(e.g. sodium hydride, etc.), alkali metal hydroxide (e.g. sodium
hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g.
sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen
carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen
carbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide,
sodium ethoxide, potassium tert-butoxide, etc.), alkali metal
alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g.
triethylamine, etc.), pyridine compounds (e.g. pyridine, lutidine,
picoline, 4-N,N-dimethylaminopyridine, etc.), quinoline, and the
like, preferably in the presence of organic bases such as
imidazole, triethylamine or pyridine.
The reaction may also be carded out using a starting material
having an opposite configuration at a carbon center. In this
situation, the following two additional steps are required to yield
a starting material having an epimeric hydroxyl moiety, i.e. (1)
the alcohol is oxidized to its corresponding ketone, (2) the
obtained ketone is reduced under selective conditions. Both chiral
centers having either [R]- or [S]-configuration can be obtained
selectively and separately.
In process (b), suitable reagents for selective deprotection of a
protecting group from C.sub.32 may be carefully carded out using,
but not limited to aqueous hydrogen fluoride in acetonitrile
(Newton, R. F., Reynolds, D. P., Finch, M. A. W., Kelly, D. R. and
Roberts, S. M. Tetrahedron Lett., 1979, 3891), tetraalkyl ammonium
fluoride in tetrahydrofuran (Corey, E. J. and Snider, B. B. J. Am.
Chem. Soc., 1972, 94, 2549, Corey, E. J. and Venkateswarlu, A. J.
Am. Chem. Soc., 1972, 94, 6190) or tetraalkyl ammonium
chloride-potassium fluoride in acetonitrile (Carpino, L. A. and
Sau, A. C. J. Chem. Soc., Chem. Commun. 1979, 5 14) wherein an
alkyl group as defined above, p-toluenesulfonic acid, potassium
carbonate in anhydrous methanol (Hurst, D. T. and MaInnes, A. G.
Can. J. Chem., 1965, 43, 2004), citric acid in methanol (Bundy, G.
L. and Peterson, D. C. Tetrahedron Lett., 1978, 41), acetic
acid:water (3:1) (Corey, E. J. and Varma, R. K. J. Am. Chem. Soc.,
1971, 93, 7319), Dowex 50W-X8 in methanol (Corey, E. J., Ponder, J.
W. and Ulrich, P. Tetrahedron Lett., 1980, 21, 137), boron
trifluoride etherate in chloroform (Kelly, D. R., Roberts, M. S.
and Newton, R. F. Synth. Commun. 1979, 9, 295), methanolic hydrogen
fluoride (Hanessian, S. and Lavallee, P. Can. J. Chem., 1975, 53,
2975; ibid., 1977, 55, 562), and pyridinuim fluoride in
tetrahydrofuran (Nicolaou, K. C., Seitz, S. P., Pavia, M. R. and
Petasis, N. A. J. Org. Chem., 1979, 44, 40 11), pyridinium
p-toluenesulfonate in ethanol (Prakash, C., Saleh, S. and Blair, I.
A. Tetrahedron Lett., 1989, 30, 19), N-bromosuccinimide in
dimethylsulfoxide (Batten, R. J. et al., Synthesis, 1980, 234), and
tetraethyldiboroxane in the presence of catalytic amounts of
trimethylsilyl triflate (Dahlhoff, W. V. and Taba, K. M.,
Synthesis, 1986, 561).
The reaction is usually conducted under from cooling to heating,
preferably from 0.degree. C. to 50.degree. C. The reaction may
require 20 minutes to one day, depending on the reagent and
temperature chosen.
In process (c), suitable reagents for activation of an alcohol
include acetic anhydride, trifluoromethanesulfonic anhydride
(triflic anhydride), fluorosulfonic anhydride, methanesulfonyl
chloride (mesyl chloride), p-toluenesulfonyl chloride (tosyl
chloride), trifluoroacetic anhydride, trifluoroacetyl chloride,
o-nitrobenzenesulfonyl chloride, 1-methyl-2-fluoropyfidinium salt
and the like.
The activation may be carried out in a solvent which does not
adversely affect the reaction (e.g., diethylether, dichloromethane,
tetrahydrofuran, chloroform or N,N-dimethylformarnide or a mixture
thereof). The reaction may require cooling or heating, depending on
the activation method chosen. Further, the reaction is preferably
conducted in the presence of an organic or inorganic base such as
an alkaline earth metal (e.g. calcium, etc.), alkali metal hydride
(e.g. sodium hydride, etc.), alkali metal hydroxide (e.g. sodium
hydroxide, potassium hydroxide, etc.), alkali metal carbonate (e.g.
sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen
carbonate (e.g. sodium hydrogen carbonate, potassium hydrogen
carbonate, etc.), alkali metal alkoxide (e.g. sodium methoxide,
sodium ethoxide, potassium tert-butoxide, etc.), alkali metal
alkanoic acid (e.g. sodium acetate, etc.), trialkylamine (e.g.
triethylamine, etc.), pyridine compounds (e.g. pyridine, lutidine,
picoline, 4-N,N-dimethylaminopyridine, etc.), quinoline, and the
like, preferably in the presence of organic bases such as
triethylamine or pyridine.
The reaction is usually conducted under from cooling to heating,
preferably from -70.degree. C. to 50.degree. C. The reaction may
require 20 minutes to one day, depend on the reagent and
temperature chosen.
In process (d), a variety of compounds may be prepared from the
displacement reactions. An activated hydroxyl group may be reacted
with a primary or secondary amine (as defined above and below). The
displacement reaction may be carried out in a solvent which does
not adversely affect the reaction (e.g. chloroform,
dichloromethane, tetrahydrofuran, pyridine, dimethylsulfoxide,
N,N-dimethylformamide, hexamethylphosphoramide, etc. or a mixture
thereof). The reaction may be conducted above, at, or below ambient
temperature, preferably from 0.degree. C. to 50.degree. C. The
reaction may require 20 minutes to one week, depend on the reagent
chosen.
In process (e), a final deprotection of C-24 protecting group may
be carried out according to the method described in process
(c).
The compounds, processes and uses of the present invention will be
better understood in connection with the following examples, which
are intended as an illustration of and not a limitation upon the
scope of the invention. Both below and throughout the
specification, it is intended that citations to the literature are
expressly incorporated by reference.
EXAMPLE 1
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.tert-butyldimethylsilyloxy; R.sup.104
.dbd.tert-butyldimethylsilyloxy; R.sup.105 .dbd.H
Ascomycin (25 g, 0.032 mol) was dissolved in a solution of
imidazole (43.03 g, 0.64 mol) in dry N,N-dimethylformamide (500 mL)
and tert-butyldimethylchlorosilane (47.64 g, 0.32 mol) was added in
portions and stirred at room temperature for 24 hours.
N,N-dimethylformamide and excess tert-butyldimethylchlorosilane
were removed by evaporation (35.degree. C. water bath) under high
vaccum. The solid residue was dissolved in 350 mL of ethyl acetate,
and the ethyl acetate layer was washed with saturated ammonium
chloride aqueous solution (200 mL.times.3), 10%-NaHSO.sub.4 (200
mL.times.3), brine, saturated NaHCO.sub.3 (200 mL.times.3), and
brine (200 mL.times.3). After dired over MgSO.sub.4, solvent was
removed in vacuo and the solid residue was purified by silica gel
chromatography, followed by HPLC eluting with 5% acetone in hexane
providing the title compound (27 g) in 84% yield. MS (FAB) m/z:
M+K=1058.
EXAMPLE 2
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.tert-butyldimethylsilyloxy; R.sup.104
.dbd.OH; R.sub.10 .dbd.H
To a solution of 48% hydrogen fluoride aqueous solution (5 mL) was
added Example 1 (32 g, 0.031 mol) in acetonitrile (500 mL), and the
mixture was stirred at room temperature for 90 minutes. It was
cooled to 0.degree. C. in an ice bath, and solid NaHCO.sub.3 was
added to the reaction mixture. It was stirred for 1 hour and solid
was removed by filtration. Acetonitrile was removed in vacuo and
ethyl acetate (500 mL) was added to the residue, and the organic
layer was washed with 10%--NaHCO.sub.3 (300 mL.times.3), brine (250
mL), 10%-NaHSO.sub.4 (300 mL.times.3), and brine (350 mL.times.3),
and dried over anhydrous sodium sulfate. Evaporation of the solvent
gave 35 g of crude title compound which was purified by silica gel
column chromatography, followed by HPLC eluting with 25%-acetone in
hexane. 24.28 g (85%) of pure compound was obtained. MS (FAB) m/z:
M+K=844;
In addition to the title compound, unreacted starting material
(Example 1, 1.5 g) and ascomycin (500 mg) were isolated as a pure
form.
EXAMPLE 3
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.-ethyl; R.sup.102
.dbd.tert-butyldimethylsilyloxy; R.sup.104
.dbd.O-trifluoromethanesulfonyl; R.sup.105 .dbd.H
The product of Example 2 (4.0 g, 4.42 mmol) was dissolved in 20 mL
of methylene chloride at 0.degree. C. pyridine (3.57 mL, 44.2
mmol), followed by trifluoromethanesuffonic acid anhydride (0.74
mL, 4.42 mmol) were carefully added to the reaction mixture. It was
stirred at 0.degree. C. for 20 minutes and the solvent was removed.
Ethyl acetate (50 mL) was added to the residue. The organic layers
were washed with brine, saturated NaHCO.sub.3 (20 mL.times.3),
brine (20 mL), 10%-NaHSO.sub.4 (20 mL.times.3), brine (20
mL.times.3) and dried over anhydrous sodium sulfate. After the
solvent was removed, the title compound was obtained in
quantitative yield (4.2 g). This compound was used for the
displacement reaction without further purification and
characterization.
EXAMPLE 4
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl: R.sup.102
.dbd.H; R.sup.103 .dbd.tert-butyldimethylsilyloxy; R.sup.104
.dbd.H; m=0; n=1; R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.methyl
The product of Example 3 (2.1 g, 2.03 mmol) was dissolved in 10 mL
of freshly distilled methylene chloride, 1-methylpiperazine (1.24
mL, 10.15 mmol) and triethylamine (0.85 mL, 6.09 mmol) were added,
and the reaction was then stirred at 50.degree. C. for 5 hours and
at room temperature for one over night. The reaction mixture was
directly poured onto silica gel column and eluted to obtain
semi-pure title compound (925 mg) in 46% yield. MS (FAB) m/z:
M+K=1026. M+H=988.
EXAMPLE 5
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.methyl
The product of Example 4 (920 mg, 0.93 mmol) was dissolved in 10 mL
of acetonitrile: water (9:1), 48% hydrogen fluoride aqueous
solution [48%-HF] (0.6 mL) was added, and the reaction was then
stirred at room temperature for 5 hours. It was cooled to 0.degree.
C. in an ice bath, and solid NaHCO.sub.3 was added to the reaction
mixture. It was stirred for 0.5 hour and solid was removed by
filtration. Acetonitrile was removed in vacuo and the residue was
purified by reverse phase HPLC (RP-HPLC), eluting with
acetonitrile-water-0.01% trifluoroacetic acid system. 290 mg of
pure title compound was obtained. MS (FAB) m/z: M+H=874, M+K=912;
mp=132.degree. C. (dec.)
EXAMPLE 6
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.-tert-butyldimethylsilyloxy; R.sup.104
.dbd.H; m=0; n=1; R.sup.3 .dbd.R.sup.4 .dbd.H; R.sup.1
.dbd.benzyl
The product of Example 3 (2.1 g, 2.03 mmol) was dissolved in 8 mL
of freshly distilled methylene chloride, 1-benzylpiperazine (1.06
mL, 6.1 mmol) and triethylamine (0.85 mL, 6.1 mmol) were added, and
was then stirred at 45.degree. C. for 5 hours. The reaction mixture
was directly poured onto silica gel column and eluted to obtain
semi-pure title compound (1.52 g). It was then purified by HPLC,
eluting with 30% acetone-hexane. 660 mg of pure title compound was
isolated in 31% yield. MS (FAB)m/z: M+K=1102. M+H=1064.
EXAMPLE 7
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH: R.sup.104 .dbd.H; m=0: n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.benzyl
The product of Example 6 (1.3 g, 1.22 mmol) was dissolved in 35 mL
of acetonitrile, 48% hydrogen fluoride aqueous solution
[48%-HF](2.2 mL) was added, and the reaction was then stirred at
room temperature for 8 hours. The reaction was quenched by the
addition of saturated NaHCO.sub.3 solution and the product was
extracted with 50 mL of ethyl acetate (x2). The ethyl acetate layer
was washed with 10%-NaHCO.sub.3, brine and dried over anhydrous
sodium sulfate. Evaporation of the solvent gave 1 g of crude fie
compound was obtained. This was purified by RP-HPLC, eluting with
acetonitrile-water-0.01%-trifluoroacetic acid system. 330 mg of the
pure title compound was obtained. MS (FAB) m/z: M+H=950, M+K=988;
mp=114.degree.-116.degree. C.
EXAMPLE 8
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.tert-butyldimethylsilyloxy; R.sup.104
.dbd.H; m=0; n=1: R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.phenyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-phenylpiperazine, provided the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-penylpiperazine (1.53 mL, 6.07 mmol), and triethylamine (1.17 mL,
5.05 mmol) in 10 mL of methylene chloride were used. 660 mg of the
pure title compound was isolated in 32% yield. MS (FAB) m/z.
M+K=1088. M+H=1050.
EXAMPLE 9
Formula I: R.sup.100 .dbd.H; R.sup.102 .dbd.ethyl; R.sup.103
.dbd.H; R.sup.104 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.phenyl
Following the procedure of Example 5, the product of Example 8 (250
mg, 0.24 mmol), 48%-HF (0.5 mL) in 10 mL of acetonitrile were used.
202 mg of the pure title compound was isolated after purified by
RP-HPLC. MS (FAB) m/z: M+K=974. M+H=936. mp=119.degree. C.
(dec.)
EXAMPLE 10
Formula I; R.sup.100 .dbd.H: R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H: R.sup.103 .dbd.tert-butyldimethylsilyloxy; R.sup.104
.dbd.H; m=0; n=1; R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.tert-butyloxycarbonyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-tert-butyloxycarbonylpiperazine, provided
the desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-tert-butyloxycarbonylpiperazine (1.13 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
were used. 670 mg of the pure title compound was isolated in 31%
yield. MS (FAB) m/z: M+K=1112. M+H=1074.
EXAMPLE 11
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H: R.sup.1
.dbd.tert-butyloxycarbonyl
Following the procedure of Example 5, the product of Example 10
(660 mg, 0.65 mmol), 48%-HF (3 mL) in 30 mL of acetonitrile were
used. 279 mg of the pure title compound was isolated after purified
by RP-HPLC. MS (FAB) m/z: M+K=998.
EXAMPLE 12
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH: R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.[4-nitrobenzyl]
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[4-nitrobenzyl]piperazine, provided the
desired compound. To a solution of piperazine (2 g, 0.023 mol) in
10 mL of ethanol added a solution of 4-nitrobenzyl bromide (5 g,
0.023 mol) in 20 mL of warm ethanol. It was gently refluxed for 1
hour and stirred at room temperature for one over night. The
resulting white precipitate was filtered, washed with a small
amount of cold ethanol, and dried to yield
1-[4-nitrobenzyl]piperazine hydrobromide (3 g). MS m/z M+H=222,
H.sup.1 --NMR (in MeOH-d.sub.4) .delta.=2.7 (t, 4H, piperazine),
3.25 (t, 4H, piperazine), 3.75 (s, 2H, benzyl), 7.62 (d, 2H,
aromatic), 8.20 (d, 2H, aromatic). The obtained
1-[4-nitrobenzyl]piperazine hydrobromide (3 g, 9.93 mmol) was
dissolved in 60 mL of 3N sodium hydroxide aqueous solution and
stirred at room temperature for 30 minutes. The product was
extracted with ethyl acetate (50 mL.times.3), and the combined
ethyl acetate layer was washed with brine, dried over anhydrous
sodium sulfate. Solvent was removed to obtain 1.7 g of
1-[4-nitrobenzyl]piperazine in 78% yield. MS m/z M+H=222, H.sup.1
-NMR (in MeOH-d4) .delta.=2.45 (t, 4H, piperazine), 2.90 (t, 4H,
piperazine), 3.55 (s, 2H, benzyl), 7.52 (d, 2H, aromatic), 8.50 (d,
2H, aromatic).
The product of Example 3 (2.1 g, 2.03 mmol),
1-[4-nitrobenzyl]piperazine (1.7 g, 8.1 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. The
reaction was carried out at 45.degree. C. for 15 hours. 1.07 g of
semi-pure compound was isolated in 48% yield. MS (FAB) m/z:
M+K=1147. M+H=1109.
The obtained product (1.0 g, 0.9 mmol) was treated with 48%-HF (4
mL) in 30 mL of acetonitrile in the procedure described in Example
5, except stirred at 45.degree. C. for 3 hours. 554 mg of the pure
title compound was isolated in 50% yield after RP-HPLC. MS (FAB)
m/z: M+K=1033. M+H=996. mp=113.degree. C. (dec.)
EXAMPLE 13
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl: R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H: m=0; n=1; R.sup.3
R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .beta.-naphthylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-.beta.-naphthylmethylpiperazine, provided
the desired compound. To a solution of piperazine (2.0 g, 0.023
mol) in 15 mL of ethanol added a solution of
(2-bromomethyl)naphthalene (5 g, 0.023 mol) in 15 mL of warm
ethanol. It was stirred at 55.degree. C. for 1 hour and stirred at
room temperature for one over night. The resulting precipitate was
filtered, washed with ethyl acetate (20 mL.times.2), and dried to
yield 1-naphthylmethylpiperazine hydrobromide (2.3 g). MS m/z
M+H=227, H.sup.1 -NMR (in MeOH-d.sub.4) .delta.=2.85 (t, 4H,
piperazine), 3.20 (t, 4H, piperazine), 3.72 (s, 2H, benzyl), 7.45
(m, 3H, aromatic), 7.70 (s, 2H, aromatic), 7.80 (3, 3H, aromatic).
The obtained 1-naphthylmethylpiperazine hydrobromide (2.2 g, 7.16
mmol) was dissolved in 50 mL of 3 N sodium hydroxide aqueous
solution and stirred at room temperature for 30 minutes. The
product was extracted with ethyl acetate (50 mL.times.3), and the
combined ethyl acetate layer was washed with brine, dried over
anhydrous sodium sulfate. Solvent was removed to obtain 1.2 g of
1-[naphthylmethyl]piperazine in 75% yield. MS m/z M+H=227, H.sup.1
-NMR (in MeOH-d.sub.6) .delta.=2.5 (m, 4H, piperazine), 2.95 (t,
4H, piperazine), 3.55 (s, 2H, benzyl), 7.74 (m, 3H, aromatic), 7.72
(s, 2H, aromatic), 7.79 (m, 3H, aromatic).
The product of Example 3 (2.1 g, 2.03 mmol),
1-naphthylmethylpiperazine (1.84 g, 8.1 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. 860
mg of pure compound was isolated in 38% yield. MS (FAB) m/z:
M+H-1114. The obtained product (850 mg, 0.76 mmol) was treated with
48%-HF (4 mL) in 30 mL of acetonitrile in the procedure described
in Example 5. 413 mg of the pure title compound was isolated after
purified by RP-HPLC in 41% yield. MS (FAB) m/z: M+K =1038.
M+H=1000. mp=125.degree.-126.degree. C.
EXAMPLE 14
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 H;
Following the procedure of Example 6, but replacing
1-benzylpiperazine with piperidine, provided the desired compound.
The product of Example 3 (2.1 g, 2.03 mmol), piperidine (0.6 mL,
6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride were used. 1.01 g of pure compound was isolated
in 55% yield. MS (FAB) m/z: M+H=973. M+K=1011.
The obtained product (1.0 g, 1.03 mmol) was treated with 48%-HF (3
mL) in 40 mL of acetonitrile in the procedure described in Example
5. 560 mg of the pure title compound was isolated in 56% yield. MS
(FAB) m/z: M+K=897. M+H=859. mp=100.degree.-101.degree. C.
EXAMPLE 15
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 OH: R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.formyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-piperazinecarboxaldehyde, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-piperazinecarboxaldehyde (0.62 mL, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride were used. It
was stirred at 45.degree. C. for 15 hours. 270 mg of pure compound
was isolated in 13% yield. MS (FAB) m/z: M+H=1002. M+K=1040.
The obtained product (260 mg, 0.26 mmol) was treated with 48%-HF (1
mL) in 15 mL of acetonitrile in the procedure described in Example
5. 176 mg of the pure title compound was isolated in 68% yield. MS
(FAB) m/z: M+H =888. M+K=926. mp=126.degree.-128.degree. C.
EXAMPLE 16
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H: R.sup.103 .dbd.OH: R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2 and R.sup.2' taken
together to form --O(CH.sub.2).sub.i O-- wherein i=2
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 4-piperidone ethylene ketal, provided the
desired compound. The product of Example 3 (2.0 g, 1.9 mmol),
4-piperidone ethylene ketal (0.742 mL, 5.7 mmol), and triethylamine
(0.81 mL, 6.09 mmol) in 10 mL of methylene chloride were used. 1.03
g of pure compound was isolated in 54% yield. MS (FAB) m/z:
M+H=1031. M+K=1069.
The obtained product (1.0 g, 0.97 1 mmol) was treated with 48%-HF
(3 mL) in 35 mL of acetonitrile in the procedure described in
Example 5. 574 mg of the pure title compound was isolated in 57%
yield. MS (FAB) m/z: M+H=917. M+K=955. mp=109.degree.-110.degree.
C.
EXAMPLE 17
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 =2-hydroxyethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[2-hydroxyethyl]piperazine, provided the
desired compound. The product of Example 3 (2.0 g, 1.9 mmol),
1-[2-hydroxyethyl]piperazine (0.71 mL, 5.7 mmol), and triethylamine
(0.81 mL, 5.7 mmol) in 10 mL of methylene chloride were used. 970
mg of pure compound was isolated in 49% yield. MS (FAB) m/z:
M+H=1018. M+K=1056.
The obtained product (960 mg, 0.94 mmol) was treated with 48%-HF (4
mL) in 40 mL of acetonitrile in the procedure described in Example
5. 414 mg of the pure title compound was isolated in 49% yield. MS
(FAB) m/z: M+H=904. M+K=942.
EXAMPLE 18
Formula I: R.sup.100 .dbd.H: R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; X=oxygen
Following the procedure of Example 6, but replacing
1-benzylpiperazine with morpholine, provided the desired compound.
The product of Example 3 (2.0 g, 1.9 mmol), morpholine (0.51 mL,
5.7 mmol), and triethylamine (0.81 mL, 5.7 mmol) in 10 mL of
methylene chloride were used. 780 mg of pure compound was isolated
in 42% yield. MS (FAB) m/z: M+H=975. M+K=1013.
The obtained product (780 mg, 0.80 mmol) was treated with 48%-HF (3
mL) in 35 mL of acetonitrile in the procedure described in Example
5. 457 mg of the pure title compound was isolated in 59% yield. MS
(FAB) m/z: M+H =861. M+K=899. mp=107.degree.-108.degree. C.
EXAMPLE 19
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.2-(2-hydroxyethoxy)ethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[2-(2-hydroxyethoxy)ethyl]piperazine,
provided the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), 1-{2-(2-hydroxyethoxy)ethyl]piperazine (0.998 mL, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride were used. 1.2 g of pure compound was isolated in 56%
yield. MS (FAB) m/z: M+H=1062. M+K=1100.
The obtained product (1.2 g, 1.13 mmol) was treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5, except reaction time was 2.5 hours. 580 mg of the pure title
compound was isolated in 53% yield. MS (FAB) m/z: M+H =948.
M+K=986. mp=102.degree.-104.degree. C.
EXAMPLE 20
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyridyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(2-pyridyl)piperazine, provided the
desired compound. The product of Example 3 (2.0 g, 1.93 mmol),
1-(2-pyridyl)piperazine (0.881 mL, 5.79 mmol), and triethylamine
(0.81 mL, 5.79 mmol) in 10 mL of methylene chloride are used and
stirred at 45.degree. C. for one over night. 580 mg of pure
compound was isolated after silica gel column chromatography,
followed by normal phase HPLC purification in 29% yield. MS (FAB)
m/z: M+H=1051. M+K=1089.
The obtained product (570 mg, 0.543 mmol) was treated with 48%-HF
(4 mL) in 25 mL of acetonitrile in the procedure described in
Example 5, except reaction time was 4 hours. 400 mg of the pure
title compound was isolated in 63% yield. MS (FAB) m/z: M+H =937.
M+K=975. mp=110.degree. C. (dec.).
EXAMPLE 21
Formula I; R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3 .dbd.R.sup.4
.dbd.R.sup.5 .dbd.H; 2-pyridyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(2-pyrimidyl)piperazine, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-(2-pyrimidyl)piperazine (0.996 mL, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. 870
mg of pure compound was isolated after silica gel column
chromatography, followed by normal phase HPLC purification in 41%
yield. MS (FAB) m/z: M+H-1052. M+K=1090.
The obtained product (0.86 g, 0.82 mmol) was treated with 48%-HF (4
mL) in 30 mL of acetonitrile in the procedure described in Example
5, except reaction time was 3.5 hours. 380 mg of the pure title
compound was isolated in 40% yield. MS (FAB) m/z: M+H =938.
M+K=976. mp=110.degree.-111.degree. C.
EXAMPLE 22
Formula I; R.sup.100 .dbd.H; R.sup.101 ethyl: R.sup.102 .dbd.H;
R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0: n=1; R.sup.1 .dbd.R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H
Commercially available N-tert-butyloxycarbonyl-piperazine (0.5 g,
2.68 mmol) was dissolved in 5 mL of THF:water (1:1) and cooled in
an ice bath. Triethylamine (0.748 mL, 5.4 mmol), followed by
benzyloxycarbonyl chloride (0.575 mL, 3.21 mmol) in diethyl ether
was slowly added to the reaction mixture. It was stirred at
0.degree. C. for 1.5 hours. Solvents were removed and 50 mL of
ethyl acetate was added to the residue. The ethyl acetate layer was
washed with saturated NaHCO.sub.3 (20 mL.times.3), brine (20
mL.times.3), and dried over anhydrous sodium sulfate.
N-tert-butyloxycarbonyl-N'-benzyloxycarbonyl-piperazine (1.0 g) was
obtained after evaporated to dryness in quantitative yield. MS:
M+NH.sub.4 =338. M+H.sup.+ =321.
N-tert-butyloxycarbonyl--N'-benzyloxycarbonyl-piperazine (1.8 g,
3.13 mmol) was dissolved in 10 mL of 4N-HCl/dioxane. It was stirred
at room temperature for 30 minutes. The reaction mixture was cooled
in an ice bath, 1N-NaOH solution was carefully added to the mixture
to adjust pH above 10. Ethyl acetate (50 mL.times.3) was used to
extract the compound. The combined ethyl acetate layers were washed
with brine, dried over anhydrous sodium sulfate. After removal of
the solvent, 1.1 g of N-benzyloxycarbonyl-piperazine was obtained
in quantitative yield.
Following the procedure of Example 6, but replacing
1-benzylpiperazine with N-benzyloxycarbonyl-piperazine, provided
the desired compound. The product of Example 3 (1.1 g, 1.06 mmol),
N-benzyloxycarbonyl-piperazine (700 mg, 3.18 mmol), and
triethylamine (0.44 mL, 3.15 mmol) in 5 mL of methylene chloride
were used. 339 mg of pure compound (C.sub.32
--N-benzyloxycarbonyl-piperazinyl-C.sub.24 -TBDMS-Ascomycin) was
isolated in 29% yield. MS (FAB) m/z: M+H=1108. M+K=1146.
The above obtained product (329 mg, 0,297 mmol) was treated with
48%-HF (0.55 mL) in 10 mL of acetonitrile in the procedure
described in Example 5. 316 mg of semi pure compound
(C-32-N-benzyloxycarbonyl-piperazinyl-Ascomycin) was isolated. This
was directly used for the next reaction without further
purification.
The obtained product (317 mg, 0.32 mmol) was carefully hydrogenated
in 40 mL of methanol in the presence of 10%-palladium on charcoal
until theoretical mount of hydrogen gas was consumed. 290 mg of
crude product was purified by reverse phase-HPLC. 117 mg of the
pure title compound was obtained in 47% yield. MS (FAB) m/z: M+H
=860. M+K=898. mp=132.degree. C. (dec).
EXAMPLE 23
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.3-pyridyl
3-Bromopyridine (0.963 mL, 10 mmol) and piparazine (0.861 g, 10
mmol) are gently refluxed in 20 mL of absolute ethanol until the
starting materials are disappeared on TLC. Ethanol is removed in
vacuo to obtain 1-[3-pyridyl]piperazine hydrochloride. The
hydrochloride salt is removed according to the procedure described
in Example 22 to yield 1-[3-pyridyl]piperazine. Following the
procedure of Example 6, but replacing 1-benzylpiperazine with
1-[3-pyridyl]piperazine, provides the desired compound. The product
of Example 3 (2.1 g, 2.03 mmol), 1-[3-pyridyl]piperazine (6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.2 g, 1.13 mmol) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5. The pure title compound is
isolated.
EXAMPLE 24
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.4-pyridyl
4-Bromopyridine hydrochloride (2.25 g, 11.61 mmol) and piparazine
(5 g, 58.05 mmol) were dissolved in 10 mL of absolute ethanol and
replaced into a sealed tube. It was kept in 95.degree. C. oil bath
for 5 hours and allowed to stand at room temperature for one over
night, The white precipitate was filtered off, washed with a small
amount of cold ethanol, and the filtrate was concentrated in vacuo
to obtain 1-[4-pyridyl]piperazine hydrobromide hydrochloride salt
with a contamination of unreacted piperazine. MS m/z M+H =165. H
1--NMR (in CDC.sub.13) .delta.=2.95 (m, 4H), 3.36 (t, 4H), 6.82
(2H, aromatic), 8.10 (2H, aromatic). The obtained
1-[4-pyridyl]piperazine hydrobromide hydrochloride salt (1.0 g) was
dissolved in 50 mL of 3N sodium hydroxide aqueous solution and
stirred at room temperature for 15 minutes. The product was
extracted with ethyl acetate (50 mL.times.3) and the combined ethyl
acetate layer was washed with brine (50 mL.times.2), dried over
anhydrous sodium sulfate. The solvent was removed in vacuo to
obtain 450 mg of 1-[4-pyridyl]piperazine in 77% yield. MS m/z
M+H=165. H.sup.1 -NMR (in CDCl.sub.3) .delta.=3.00 (m, 4H), 3.30
(t, 4H), 6.65 (2H, aromatic), aromatic). Following the procedure of
Example 6, but replacing 1-benzylpiperazine with
1-[4-pyridyl]piperazine, provides the desired compound. The product
of Example 3 (2. 1 g, 2.03 mmol), 1-[4-pyridyl]piperazine (999 mg,
6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.2 g, 1.13
mmol) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to yield the pure title
compound.
EXAMPLE 25
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0: n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.methanesulfonyl
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved
in 5 mL of THF: water (1:1) and cooled in an ice bath.
Triethylamine (1.45 mL, 10.68 mmol), followed by methanesulfonyl
chloride (0.50 mL, 6.44 mmol) in 5 mL of ether were added, and
stirred at 0.degree. C. for 1 hour and at room temperature for 2
hours. Solvents were removed and 40 mL of ethyl acetate was added
to the residue. The ethyl acetate layer was washed with brine (30
mL.times.3) and dried over anhydrous sodium sulfate. After
filtered, the filtrate was concentrated in vacuo to yield 1.314 g
of N-tert-butyloxycarbonyl-N'-methanesulfonyl-piperazine in 93%
yield. MS m/z M+NH.sub.4 =282. H.sup.1 -NMR (in CDCl.sub.3)
.delta.=1.48 (s, 9H, Boc), 2.79 (s, 3H, S-CH.sub.3), 3.18 (t, 4H,
piperazine), 3.55 (t, 4H, piperazine). The obtained
N-tert-butyloxycarbonyl-N'-methanesulfonyl-piperazine (1.3 g, 4.97
mmol) was dissolved in 10 mL of 20% trifluoroacetic acid in
methylene chloride and stirred at room temperature for 30 minutes.
Solvent and trifluoroacetic acid were removed to obtain
N-methanesulfonylpiperazine trifluoroacetic acid salt in
quantitative yield. MS m/z M+H=165, H.sup.1 -NMR (in MeOH-d.sub.4)
.delta.=2.95 (s, 3H, S-CH.sub.3), 3.35 (m, 4H, piperazine), 3.5 (m,
4H, piperazine). The obtained N-methanesulfonyl trifluoroacetic
acid salt (2.2 g) was dissolved in 30 mL of acetonitrile and cooled
in an ice bath. Solid sodium bicarbonate was added to the
acetonitrile solution and stirred for 2 hours. Solid was filtered
off and the filtrate was concentrated in vacuo to yield
N-methanesulfonylpiperazine in quantitative yield. MS m/z M+H =165,
M+NH.sub.4 =182; H.sup.1 -NMR (in MeOH-d.sub.4) .delta.=2.85 (s,
3H, S-CH.sub.3), 2.95 (t, 4H, piperazine), 3.22 (t, 4H,
piperazine).
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-methanesulfonylpiperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated salt free form of 1-methanesulfonylpiperazine (999 mg,
6.09 mmol), and methylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to yield the pure title
compound.
EXAMPLE 26
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; diethylphosphoryl
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved
in 5 mL of THF: water (1:1) and cooled in an ice bath.
Triethylamine (1.45 mL, 10.68 mmol), followed by
diethylchlorophosphate (1.16 mL, 8.01 mmol) in 5 mL of ether were
added, and stirred at 0.degree. C. for 1 hour and at room
temperature for 2 hours. Solvents were removed and 40 mL of ethyl
acetate was added to the residue. The ethyl acetate layer was
washed with brine (30 mL.times.3) and dried over anhydrous sodium
surf ate. After filtered, the filtrate was concentrated in vacuo to
yield 1.5 g of
N-tert-butyloxycarbonyl--N'-diethylphosphoryl-piperazine in 88%
yield as an oil. MS m/z M+H=323, M+NH.sub.4 =340. H.sup.1 -NMR (in
CDCl.sub.3) .delta.=1.32 (t, 6H, 2.times.CH.sub.3), 1.48 (s, 9H,
Boc), 3.1 (m, 4H, piperazine), 3.37 (t, 4H, piperazine), 4.05 (m,
4H, 2.times.OCH.sub.2). The obtained
N-tert-butyloxycarbonyl--N'-diethylphosphoryl-piperazine (1.5 g,
4.66 mmol) was dissolved in I 0 mL of 10% trifluoroacetic acid in
methylene chloride and stirred at room temperature for 30 minutes.
Solvent and trifluoroacetic acid were removed to obtain 1.6 g of
N-diethylphosphorylpiperazine trifluoroacetic acid salt in
quantitative yield. MS m/z M+H=223, H.sup.1 -NMR (in MeOH-d.sub.4)
.delta.=1.35 (m, 6H, 2.times.CH.sub.3), 3.19 (m, 4H, piperazine),
3.37 (m, 4H, piperazine), 4.05 (m, 4H, 2.times.OCH.sub.2).
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-diethylphosphorylpiperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated salt free form of N-diethylphosphorylpiperazine (1.358
g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to yield the pure title
compound.
EXAMPLE 27
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.1-pyrrolidinocarbonylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[1-pyrrolidinocarbonylmethyl]piperazine,
provided the desired compound. The product of Example 3 (2.0 g,
1.93 mmol), 1-[1-pyrrolidinocarbonylmethyl]piperizine (1.14 g, 5.79
mmol), and triethylamine (0.81 mL, 5.79 mmol) in 10 mL of methylene
chloride were used. 1.4 g of pure compound was isolated in 67%
yield. MS (FAB) m/z: M+H=1085. M+K=1123.
The obtained product (1.2 g, 1.11 mmol) was treated with 48%-HF (4
mL) in 45 mL of acetonitrile in the procedure described in Example
5, except reaction time was 3.5 hours. 620 mg of the pure title
compound was isolated in 52% yield. MS (FAB) m/z: M+H =971.
M+K=1009. mp=110.degree.-112.degree. C.
EXAMPLE 28
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.1-morpholinocarbonylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[1-morpholinocarbonylmethyl]piperazine,
provided the desired compound. The product of Example 3 (2.0 g,
1.93 mmol), 1-[1-morpholinoocarbonylmethyl]piperizine (1.23 g, 5.79
mmol), and triethylamine (0.81 mL, 5.79 mmol) in 10 mL of methylene
chloride were used. 1.1 g of pure compound was isolated in 55%
yield. MS (FAB) m/z: M+H=1101.
The obtained product (1.0 g, 0.909 mmol) was treated with 48%-HF (4
mL) in 45 mL of acetonitrile in the procedure described in Example
5. 624 mg of the pure title compound was isolated in 56% yield. MS
(FAB) m/z: M+H =987. M+K=1025. mp=112.degree.-113.degree. C.
EXAMPLE 29
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.cyclopropyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-cyclopropylpiperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-cyclopropylpiperazine (6.09 mmol), and triethylamine (0.85 mL,
6.09 mmol) in 10 mL of methylene chloride are used. The obtained
product (1.0 g) is treated with 48%HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 30
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.cyclobutyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-cyclobutylpiperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated free base form of 1-cyclobutylpiperazine (854 mg, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 31
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.cyclopentyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-cyclopentylpiperazine, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated free base form of 1-cyclopentylpiperazine (934 mg,
6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride were used. It was gently refluxed at 45.degree.
C. for one over night. 1.07 g of the title compound with C.sub.24
-TBDMS group was isolated in 51% yield after silica gel
chromatography. MS(FAB) m/z: M+H =1042. The obtained product (1.05
g, 1.008 mmol) was treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 for 4 hours.
After purified by reverse phase HPLC, the pure desirable title
compound (459 mg) was obtained in 39% yield. MS (FAB) m/z: M+K=966.
mp=124.degree.-125.degree. C.
EXAMPLE 32
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.cyclohexyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-cyclohexylpiperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated free base form of 1-cyclohexylpiperazine (1.024 g,
6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to obtain the pure title
compound.
EXAMPLE 33
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.cycloheptyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-cycloheptylpiperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated free base form of 1 -cycloheptylpiperazine (1.110 g,
6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to provide the pure tide
compound.
EXAMPLE 34
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.cyclooctyl
Following the procedures of Example 6, but replacing
1-benzylpiperazine with 1-cyclooctylpiperazine, provide the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated
free base form of 1-cyclooctylpiperazine (1.196 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 35
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.N-morpholinocarbonyl
N-tert-butyloxycarbonylpiperazine (1.0 g, 5.34 mmol) was dissolved
in 5 mL of THF: water (1: 1) and cooled in an ice bath.
Triethylamine (1.45 mL, 10.68 mmol), followed by
4-morpholinocarbonyl chloride (0.752 mL, 6.4 mmol) in 5 mL of ether
were added, and stirred at 0.degree. C. for 1 hour and at room
temperature for 2 hours. Solvents were removed and 40 mL of ethyl
acetate was added to the residue. The ethyl acetate layer was
washed with brine (30 mL x 3) and dried over anhydrous sodium
sulfate. After filtered, the filtrate was concentrated in vacuo to
yield 1.39 g of
N-tert-butyloxycarbonyl-N'-morpholinocarbonyl-piperazine in 87%
yield as a solid. MS m/z M+H=300, M+NH.sub.4 =317; H.sup.1 -NMR (in
CDCl.sub.3) .delta.=1.49 (s, 9H, Boc), 3.25 (m, 8H,
4.times.CH.sub.2), 3.52 (m, 4H), 3.65 (m, 4H). The obtained
N-tert-butyloxycarbonyl-N'-morpholinocarbonyl-piperazine (1.38 g,
4.62 mmol) was dissolved in 10 mL of 20% trifluoroacetic acid in
methylene chloride and stirred at room temperature for 1 hour.
Solvent and trifluoro acetic acid were removed to obtain
N-morpholinocarbonylpiperazine trifluoroacetic acid salt in
quantitative yield. MS m/z M+H=200, H.sup.1 -NMR (in MeOH-d.sub.4)
.delta.=3.22 (m, 4H), 3.3 (m, 4H), 3.45 (m, 4H), 3.65 (m, 4H). The
obtained N-morpholinocarbonylpiperazine trifluoroacetic acid salt
is dissolved in 30 mL of acetonitrile and cooled in an ice bath.
Solid sodium bicarbonate is added to the acetonitrile solution and
stirred for an additional 2 hours. Solid is filtered off and the
filtrate is concentrated in vacuo to yield
N-morpholinocarbonylpiperazine. Following the procedure of Example
6, but replacing 1-benzylpiperazine with
1-morpholinocarbonylpiperazine, provides the desired compound. The
product of Example 3 (2.1 g, 2.03 mmol),
1-morpholinocarbonylpiperazine (1.212 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (I.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to yield the pure title compound.
EXAMPLE 36
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2 .dbd.R.sup.2' .dbd.OH
Commercially available 4,4-piperidinediol hydrochloride (3.72 g, 20
mmol) is dissolved in 30 mL of acetonitrile and cooled in an ice
bath. Solid sodium bicarbonate is added to the acetonitrile
solution and stirred for an additional 2 hours. Solid is filtered
off and the filtrate is concentrated in vacuo to yield
4,4-piperidinediol. Following the procedure of Example 6, but
replacing 1-benzylpiperazine with 4,4-piperidinediol, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
4,4-piperidinediol (713.4 mg, 6.09 mmol), and triethylamine (0.85
mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to yield the
pure title compound.
Alteratively, the title compound is also synthesized from the
compound of Example 16. Compound of Example 16 (916 mg, 1 mmol) is
treated with 10 mL of cold dioxane: HCl (1:1) mixture until
starting material is disappeared on TLC plate. The solution is
carefully evaporated to dryness and purified by reverse phase HPLC
as has been described in Example 7.
EXAMPLE 37
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.methyl
To a solution of homopiperazine (5 g, 50 mmol) in 10 mL of ethanol
added a solution of methyl iodide (0.62 mL, 10 mmol) in 5 mL of
ethanol in a sealed tube. It was gently stirred at 95.degree. C.
for 5 hours. The resulting white precipitate was filtered, washed
with a small mount of cold ethanol, and the filtrate was
concentrated in vacuo to yield 1-methyl homopiperazine hydroiodide.
MS m/z M+H=115. The obtained 1-methylhomopiperazine hydroiodide is
convened into free base according to the procedure describing in
Example 25. Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-methyl homopiperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-methylhomopiperazine (700 mg, 6.09 mmol), and triethylamine (0.85
mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
reaction is carried out at 45.degree. C. for 15 hours. Semi-pure
compound is isolated from silica gel column chromatography.
The obtained product (1.0 g, 0.9 mmol) is treated with 48%-HF (4
mL) in 30 mL of acetonitrile in the procedure described in Example
5. The pure title compound is isolated from silica gel column
chromatography, followed by reverse phase HPLC.
EXAMPLE 38
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.piperonyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-piperonylpiperazine, provided the desired
compound. The product of Example 3 (2.0 g, 1.93 mmol),
1-piperonylpiperazine (1.275 g, 5.79 mmol), and triethylamine (0.81
mL, 5.79 mmol) in 10 mL of methylene chloride were used and stirred
at 45.degree. C. for one over night. 1.2 g of pure compound was
isolated after silica gel column chromatography, followed by normal
phase HPLC purification in 56% yield. MS (FAB) m/z: M+H=1108.
M+K=1146. The obtained product (1.2 g, 1.08 mmol) was treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5, except reaction time was 5 hours. 702 mg of the pure
title compound was isolated in 53 yield after RP-HPLC purification.
MS (FAB) m/z: M+H=994. M+K=1032. mp=115.degree.-117.degree. C.
EXAMPLE 39
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.4-acetylphenyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-piperazineacetophenone, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-piperazineacetophenone (1.244 g, 6.09 mmol), and triethylamine
(0.563 mL, 4.06 mmol) in 10 mL of methylene chloride were used. The
reaction was carried out at 45.degree. C. for one over night with
stirring. The reaction mixture was purified on silica gel cloumn
and the compound was eluted with 10% acetone in hexane to obtain
semi-pure product (1.2 g). MS (FAB) m/z: M+K=1130, M+H=1092. The
obtained product (2.0 g, 1.09 mmol) was treated with 48%-HF (3 mL)
in 30 mL of acetonitrile and then purified in the procedure
described in Example 5 to obtain the pure title compound (462 mg)
in 43% yield. MS (FAB) m/z: M+K=1016. mp=116.degree.-117.degree.
C.
EXAMPLE 40
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.(1,3-dioxolane)methyl
Commercially available glycerol formal (2.6 mL, 30 mmol) is treated
with carbon tetrabromide (11.94 g, 36 mmol) and triphenylphosphine
(11.80 g, 45 mmol) in 40 mL of methylene chloride. Fractional
distillation gives the desired bromide derivative. The obtained
bromo derivative is reacted with piperazine to yield its
hydrobromide salt, and free base is liberated by treatment of solid
sodium bicarbonate according to the method described in Example 25.
Following the procedure of Example 6, but replacing
1-benzylpiperazine with the above piparazine derivative, provides
the desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
3-(1-piperazinyl)-1,3-dioxolanemethyl (1.049 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to yield the pure title compound.
EXAMPLE 41
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.2,3-bishydroxy]propyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 3-(1-piperazinyl)- 1,2-propanediol,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), 3-(1-piperazinyl)-l,2-propanediol (975.7 mg, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 42
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyridylmethyl
Commercially available 2-pyridylcarbinol (2.89 mL, 30 mmol) is
treated with carbon tetrabromide (11.94 g, 36 mmol) and
triphenylphosphine (11.80 g, 45 mmol) in 40 mL of methylene
chloride to obtain 2-pyridylmethyl bromide. The obtained
2-pyridylmethyl bromide is reacted with piperazine to yield its
hydrobromide salt, and free base is liberated by treatment of solid
sodium bicarbonate according to the method described in Example 25.
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[2-pyridylmethyl]piperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-[2-pyridylmethyl]piperazine (1.076 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. Pure C.sub.24 -TBDMS compound is isolated. The obtained
product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to yield the
pure title compound.
EXAMPLE 43
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2 and R.sup.2' taken
together to form --O(CH.sub.2).sub.i O-- wherein i=3
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 4-piperidone propylene ketal, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
4-piperidone propylene ketal (975.2 mg, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 44
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2 .dbd.N-pyrrolidino;
R.sup.2' .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 4-pyrrolidinopiperidine, provided the
desired compound. The product of Example 3 (2.0 g, 1.93 mmol),
4-pyrrolidinopiperidine (891 mg, 5.79 mmol), and triethylamine
(0.537 mL, 3.86 mmol) in 10 mL of methylene chloride were used. The
reaction was carried out at 35.degree. C. for 5 hours with
stirring. The reaction mixture was purified on silica gel cloumn.
After the by-products were eluted with 10% acetone in hexane, the
compound was eluted with 5% methanol in methylene chloride to
obtain semi-pure product (1.2 g) in 60% yield. MS (FAB) m/z:
M+K=1080, M+H=1042. The obtained product (1.18 g, 1.13 mmol) was
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to obtain the pure title compound.
253 mg (24%), MS (FAB) m/z: M+K=928, M+H=966.
mp=122.degree.-125.degree. C.
EXAMPLE 45
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2 .dbd.N-piperidino;
R.sup.2' .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-piperidinopiperidine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-piperidinopiperidine (1.025 g, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 46
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2 .dbd.N,N-dimethylamino;
R.sup.2' .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 4-dimethylaminopiperidine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
4-dimethylaminopiperidine (1.110 g, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 47
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3 .dbd.N-pyrrolidinoethyl;
R.sup.4 .dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 2-(2--N-pyrrolidinoethyl) piperidine,
provides the desired compound. The product of Example 3 (2. 1 g,
2.03 mmol), 2-(2--N-pyrrolidinoethyl) piperidine (1.110 g, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 48
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.H; R.sup.3 .dbd.N,N-dimethylaminoethyl; R.sup.4
.dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 2-(2-dimethylaminoethyl) piperidine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), 2-(2-dimethylaminoethyl) piperidine (951.7 mg, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 49
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.H; R.sup.3 .dbd.(S)-N-methyl-2-piperidinomethyl;
R.sup.4 .dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with
(S)--N-methyl-2-[2'-piperidinomethyl]pyrrolidine, provides the
desired compound. The product of Example 3(2.1 g, 2.03 mmol),
(S)-1-methyl-2-(2'-piperidinomethyl)pyrrolidine (1.110 g, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 50
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.H; R.sup.3 .dbd.(S)-1-[2-(pyrrolidinomethyl)];
R.sup.4 .dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with
(S)-(+)-1-(2-(pyrrolidinomethyl)pyrrolidine, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
(S)-(+)-1-(2-(pyrrolidinomethyl)pyrrolidine (939.4 mg, 6.09 mmol),
and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 51
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.H; R.sup.3 .dbd.N,N-dimethylaminomethyl; R.sup.4
.dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with N-(2-piperidylmethyl) dimethylamine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), N-(2-piperidylmethyl) dimethylamine (866 mg, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 52
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.H; R.sup.4 .dbd.N,N-diethylcarbonyl; R.sup.3
.dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with N,N-diethyl nipecotanide, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
N,N-diethyl nipecotanide (1.122 g, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 53
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; X.dbd.sulfur
Following the procedure of Example 6, but replacing
1-benzylpiperazine with thiomorpholine, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
thiomorpholine (1.122 g, 6.09 mmol), and triethylamine (612.5
.mu.L, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated With 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 54
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.3-furoyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(3-furoyl)piperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-(2-furoyl)piperazine (1.097 g, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 55
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4' .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.allyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-allylpiperazine, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated
salt free form of 1-allylpiperazine (769 mg, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 56
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.propargyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-propargylpiperazine, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol), base-treated
salt free form of 1-propargylpiperazine (756 mg, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 57
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4.dbd. .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyrazinyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(2-pyrazinyl)piperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-(2-pyrazinyl)piperazine (1.0 g, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 58
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.ethoxycarbonyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-ethoxycarbonylpiperazine, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-ethoxycarbonylpiperazine (0.889 mL, 6.08 mmol), and triethylamine
(0.563 mL, 4.06 mmol) in 10 mL of methylene chloride were used. The
reaction was carded out at 45.degree. C. for one over night with
stirring. The reaction mixture was directly loaded on silica gel
cloumn and the compound was eluted with 20% acetone in hexane to
obtain semi-pure product (952 mg) in 45% yield. MS (FAB) m/z:
M+K=1084, M+H - 1046. The obtained product (900 mg, 0.86 mmol) was
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to obtain the pure title compound.
275 mg (34%), MS (FAB) m/z: M+K=970, M+H=932.
mp=110.degree.-112.degree. C.
EXAMPLE 59
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4.dbd. .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.ethoxycarbonylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with N-(carboethoxymethyl)piperazine, provides
the desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
N-(carboethoxymethyl)piperazine (1.049 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 60
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.2-(N,N-diethylamino)ethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[2-(diethylamino) ethyl]piperazine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), base-treated salt free form of 1-[2-(dimethylamino)
ethyl]piperazine (1.129 g, 6.09 mmol), and triethylamine (0.85 mL,
6.09 mmol) in 10 mL of methylene chloride are used. The obtained
product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 61
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.acetyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-acetylpiperazine, provided the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-acetylpiperazine (780.6 mg, 6.09 mmol), and triethylamine (0.563
mL, 4.06 mmol) in 10 mL of methylene chloride were used. The
reaction was carried out at 45.degree. C. for one over night with
stirring. The reaction mixture was purified on silica gel cloumn.
After the column was washed with 10% acetone in hexane to remove
by-products, the compound was eluted with 20% acetone in hexane,
followed by 2.5% methanol in methylene chloride to obtain product
(0.640 g) in 31% yield. MS (FAB) m/z: M+K=1054, M+H=1016. The
obtained product (638 mg, 0.629 mmol) was treated with 48%-HF (3
mL) in 30 mL of acetonitrile and then purified in the procedure
described in Example 5 to obtain the pure title compound (394 mg)
in 70% yield. MS (FAB) m/z: M+K =940, M+H =902.
mp=119.degree.-120.degree. C. (dec.).
EXAMPLE 62
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.iso-propylaminocarbonylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with isotroperenol, provided the desired
compound. The product of Example 3 (2.0 g, 1.93 mmol), base-treated
salt free form of isoproterenol (1.07 g, 5.79 mmol), and
triethylamine (0.537 mL, 3.86 mmol) in 10 mL of methylene chloride
were used. The reaction was carried out at 45.degree. C. for one
over night with stirring. The reaction mixture was purified on
silica gel cloumn. After the column was washed with 10% acetone in
hexane to remove by-products, the compound was eluted with 10%
methanol in methylene chloride to obtain semi-pure product (2.1 g).
MS (FAB) m/z: M+K=1111, M+H=1072. The obtained product (2.0 g, 1.86
mmol) was treated with 48%-HF (5 mL) in 40 mL of acetonitrile and
then purified in the procedure described in Example 5 to obtain the
pure title compound (679 mg) in 38% yield. MS (FAB) m/z: M+K =997,
M+H=959. mp=114.degree.-118.degree. C.
EXAMPLE 63
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.N-methyl-N-phenylaminocarbonylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with piperidinoacetic acid N-methylanilide,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), piperidinoacetic acid N-methylanilide (1.421 g, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to yield the pure title compound.
EXAMPLE 64
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.4' .dbd.R.sup.5 .dbd.H; R.sup.3
.dbd.N-pyrrolylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(2-piperidylmethyl) pyrrole, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated salt free form of 1-(2-piperidylmethyl) pyrrole (1.0
g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to obtain the pure title
compound.
EXAMPLE 65
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.5 .dbd.H; R.sup.4 .dbd.N-pyrrolyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with N-[3-piperidyl]pyrrole, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol)
N-[3-piperidyl]pyrrole (915 mg, 6.09 mmol), and triethylamine (0.85
mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 66
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.2-hydroxyethyl; R.sup.2' .dbd.R.sup.3 .dbd.R.sup.4
.dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 4-piperidineethanol, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
4-piperidineethanol (787 mg, 6.09 mmol), and triethylamine (0.85
mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 67
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.hydroxy; R.sup.2' .dbd.R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 4-hydroxypiperidine, provided the desired
compound. The product of Example 3 (2.0 g, 1.93 mmol),
4-hydroxypiperidine (0.585 ml, 5.79 mmol), and triethylamine (0.672
mL, 4.83 mmol) in 10 mL of methylene chloride were used. The
obtained product (1.24 g, 65%, M+H.sup.+ =989) was treated with
48%-HF (4 mL) in 40 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound (360 mg) in 33%
yield. MS (FAB) m/z: M+K.sup.+ =913, M+H.sup.+ =875.
mp=98.degree.-104.degree. C.
EXAMPLE 68
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.--C(O)NH.sub.2 ; R.sup.2' .dbd.R.sup.3 .dbd.R.sup.4
.dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 4-piperidine carboxamide, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
4-piperidine carboxamide (780.6 mg, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 69
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.3 .dbd.R.sup.5 .dbd.H; R.sup.4
.dbd.ethoxycarbonyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with ethyl nipecotate, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol), ethyl
nipecotate (957.4 mg, 6.09 mmol), and triethylamine (0.85 mL, 6.09
mmol) in 10 mL of methylene chloride are used. The obtained product
(1.0 g) is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in
the procedure described in Example 5 to obtain the pure title
compound.
EXAMPLE 70
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.3-chlorophenyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(3chlorophenyl) piperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
base-treated salt free form of 1-(3-chlorophenyl)piperazine (1.198
g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to yield the pure title
compound.
EXAMPLE 71
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-cyanophenyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(2-cyanophenyl) piperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-(2-cyanophenyl)piperazine (1. 140 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to yield the pure title compound.
EXAMPLE 72
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.3,4-dimethoxyphenyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(3,4-dimethoxyphenyl) piperazine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), base-treated salt free form of
1-(3,4-dimethoxyphenyl)piperazine (1.353 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to yield the pure title compound.
EXAMPLE 73
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.3,4,5-trimethoxyphenyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(3,4,5-trimethoxyphenyl) piperazine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), base-treated salt free form of
1-(3,4,5-trimethoxyphenyl)piperazine (1.532 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to yield the pure title compound.
EXAMPLE 74
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2'
.dbd.R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2
.dbd.acetamido
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 3-acetamidopyrrolodine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
3-acetamidopyrrolodine (780.6 mg, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 75
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2'
.dbd.R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.2
.dbd.trifluoroacetamido
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 3-[trifluoroacetamido]pyrrolodine, provides
the desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
3-[trifluoroacetamido]pyrrolodine (1.109 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 76
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3
.dbd.hydroxymethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (R)-(-)-2-pyrrolidine methanol, provided
the desired compound. The product of Example 3 (2.0 g, 1.93 mmol),
(R)-(-)-2-pyrrolidine methanol (0.571 ml, 5.79 mmol), and
triethylamine (0.538 mL, 3.86 mmol) in 10 mL of methylene chloride
were used. The obtained product (1.13 g, 60%, M+H+=989) was treated
with 48%-HF (4 mL) in 30 mL of acetonitrile in the procedure
described in Example 5 to obtain the pure title compound (260 mg)
in 27% yield. MS (FAB) m/z: M+K.sup.+ =913, M+H.sup.+ =875.
mp=90.degree. C. (dec.).
EXAMPLE 77
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.nitro
Piperazine is carefully treated with sodium nitrite and
hydrochrolic acid in aqueous media to produce N-nitopiperazine
hydrochloride. The obtained N-nitopiperazine hydrochloride (2.2 g)
is dissolved in 30 mL of acetonitrile and cooled in an ice bath.
Solid sodium bicarbonate is added to the acetonitrile solution and
stirred for 2 hours. Solid is filtered off and the filtrate is
concentrated in vacuo to yield N-nitropiperazine. Following the
procedure of Example 6, but replacing 1-benzylpiperazine with
1-nitropiperazine, provides the desired compound. The product of
Example 3 (2.1 g, 2.03 mmol), 1-nitropiperazine (792.4 mg, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 78
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; X.dbd.absent
Following the procedure of Example 6, but replacing
1-benzylpiperazine with azetidine, provides the desired compound.
The product of Example 3 (2.1 g, 2.03 mmol), azetidine (410.6
.mu.L, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL
of methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to obtain the pure title
compound.
EXAMPLE 79
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; X.dbd.sulfur
Following the procedure of Example 6, but replacing
1-benzylpiperazine with thiazolidine, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol), thiazolidine
(480.1 .mu.L, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in
10 mL of methylene chloride are used. The obtained product (1.0 g)
is treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to obtain the pure title
compound.
EXAMPLE 80
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.N-aminocarbonylamino
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-imidazolidinyl urea, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-imidazolidinyl urea (792.1 mg, 6.09 mmol), and triethylamine
(0.85 mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%-HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 81
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyrimidyl
The product of Example 103 (775 mg, 1 mmol) is treated with
trifluoromethanesulfonic acid anhydride according to the procedure
described in Example 3, and the obtained product is reacted with
1-(2-pyrimidyl)piperazine according to the method described in
Example 4. The obtained crude product is purified by the method
described in example 5 to yield the title compound.
EXAMPLE 82
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 taken together form a bond; R.sup.104 .dbd.H;
m=0; n=1; R.sup.3 .dbd.R.sup.4 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H;
R.sup.1 .dbd.2-pyrimidyl
The product of Example 102 (773 mg, 1 mmol) is treated with
trifluoromethanesulfonic acid anhydride according to the procedure
described in Example 3, and the obtained product is reacted with
1-(2-pyrimidyl)piperazine according to the method described in
Example 4. The obtained crude product is purified by the method
described in example 5 to yield the title compound.
EXAMPLE 83
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-hydroxyethyl
Compound [Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.allyl;
R.sup.102 .dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.OH; R.sup.105
.dbd.H] (25.4 g, 0.0316 mol) is dissolved in a solution of
imidazole (43.03 g, 0.64 mol) in dry N,N-dimethylformamide (500 mL)
and tert-butyldimethylchlorosilane (47.64 g, 0.32 mol) is added in
portions and stirred at room temperature for 24 hours. It is then
treated in the same fashion described in Example 1 to obtain the
compound [Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.allyl;
R.sup.102 .dbd.H; R.sup.103 =tert-butyldimethylsilyloxy; R.sup.104
=tert-butyldimethylsilyloxy; R.sup.105 .dbd.H]. The obtained
compound is treated in the same method described in Example 2 to
yield the compound [Formula I: R.sup.100 .dbd.H; R.sup.101
.dbd.allyl; R.sup.102 .dbd.H; R.sup.103
=tert-butyldimethylsilyloxy; R.sup.104 =OH; R.sup.105 .dbd.H].
The product of the above reaction (4.1 g, 4.42 mmol) is dissolved
in 20 mL of methylene chloride at 0.degree. C. pyridine (3.57 mL,
44.2 mmol), followed by trifluoromethanesulfonic acid anhydride
(0.74 mL, 4.42 mmol) are carefully added to the reaction mixture.
It is stirred at 0.degree. C. for 20 minutes and treated in the
same procedure described in Example 3 to produce the compound
[Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.allyl; R.sup.102
.dbd.H; R.sup.103 =tert-butyldimethylsilyloxy; R.sup.104
.dbd.O-trifluoromethanesulfonyl; R.sup.105 .dbd.H].
The product of the above reaction (2.2 g, 2.03 mmol) is dissolved
in 10 mL of freshly distilled methylene chloride,
1-[2-hydroxyethyl]piperazine (0.7 mL, 5.7 mmol) and triethylamine
(0.85 mL, 6.09 mmol) are added, and the reaction is then stirred at
50.degree. C. for 5 hours and at room temperature for one over
night. The reaction mixture is treated in the same manner described
in Example 6 to produce the compound [Formula I: R.sup.100 .dbd.H;
R.sup.101 .dbd.allyl; R.sup.102 .dbd.H; R.sup.103
=tert-butyldimethylsilyloxy; R.sup.104 .dbd.H; R.sup.105
=4-[2-hydroxyethyl]piperazinyl]. The product of the above reaction
(962 mg, 0.94 mmol) is reacted with 48% hydrogen fluoride aqueous
solution [48%-HF] by the method described in Example 5 to yield the
title compound.
EXAMPLE 84
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.allyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 2-pyrimidyl
The title compound is prepared following the procedure of Example
83, but replacing the compound [Formula I: R.sup.100 .dbd.H;
R.sup.101 .dbd.allyl; R.sup.102 .dbd.H; R.sup.103 =OH; R 104=OH;
R.sup.105 .dbd.H] with the compound [Formula I: R.sup.100 .dbd.H;
R.sup.101 =methyl; R.sup.102 .dbd.H; R.sup.103 =OH; R.sup.104 -OH;
R.sup.105 .dbd.H].
EXAMPLE 85
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.methyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyrimidyl
The title compound is prepared following the procedure of Example
83, but replacing 1-[2-hydroxyethyl]piperazine with
1-[2-pyrimidyl]piperazine.
EXAMPLE 86
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.n-propyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-hydroxyethyl
The title compound is prepared following the procedure of Example
83, but replacing the compound [Formula I: R.sup.100 .dbd.H;
R.sup.101 .dbd.allyl; R.sup.102 .dbd.H; R.sup.103 -OH; R.sup.104
=OH; R.sup.105 .dbd.H] with the product of Example 104, and
replacing 1-[2-hydroxyethyl]piperazine with
1-[2-hydroxyethyl]piperazinyl.
EXAMPLE 87
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.propyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyrimidyl
The title compound is prepared following the procedure of Example
83, but replacing the compound [Formula I: R.sup.100 .dbd.H;
R.sup.101 .dbd.allyl; R.sup.102 .dbd.H; R.sup.103 .dbd.OH;
R.sup.104 =OH; R.sup.105 .dbd.H] with the product of Example
104.
EXAMPLE 88
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.3-chloropropyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(3-chloropropyl) piperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-(3-chloropropyl) piperazine (1,158 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 89
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.pyrrolidinocarbonylmethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(pyrrolidinocarbonylmethyl)piperazine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol), 1-(pyrrolidinocarbonylmethyl)piperazine (1.201 g, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 90
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-aminoethyl
1-(2-aminoethyl)piperazine (1.29 g, 10 mmol) is dissolved in 20 mL
of dioxane: water (1:1) mixture and
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10
mmol) is added. The mixture is then stirred until no starting
material is detected on thin layer chromatography. The obtained
mixture is fractionally separated by silica gel chromatography,
followed by RP-HPLC to obtain
1-[2-tert-butoxycarbonylaminoethyl]piperazine. Following the
procedure of Example 6, but replacing 1-benzylpiperazine with
1-[2-tert-butoxycarbonylaminoethyl]piperazine, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-[2-tert-butoxycarbonylaminoethyl]piperazine (1.396 g, 6.09 mmol),
and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5, followed by a carefully deprotection of
N-tert-butoxycarbonyl group with 10% trifluoroacetic acid to obtain
the pure title compound.
EXAMPLE 91
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 =N-piperazinoethyl
1,1'-ethylenedipiperazine (1.98 g, 10 mmol) is dissolved in 20 mL
of dioxane: water (1:1) mixture and
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10
mmol) is added. The mixture is then stirred until no starting
material is detected on thin layer chromatography. The obtained
mixture is fractionally separated by silica gel chromatography,
followed by RP-HPLC to obtain
N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine. Following the
procedure of Example 6, but replacing 1-benzylpiperazine with
N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine, provides the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
N-[4-tert-butoxycarbonylpiperazino]ethyl-piperazine (1.817 g, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5, followed by a carefully deprotection of
N-tert-butoxycarbonyl group with 10% trifiuoroacetic acid to obtain
the pure title compound.
EXAMPLE 92
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=0; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.4 .dbd.H; R.sup.3 .dbd.--C(O)OH
Following the procedure of Example 6, but replacing
1-benzylpiperazine with proline, provides the desired compound. The
product of Example 3 (2.1 g, 2.03 mmol), proline (700 mg, 6.09
mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene
chloride are used. The obtained product (1.0 g) is treated with
48%-HF (4 mL) in 35 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 93
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.2-cyclohexylethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-[2-cyclohexylethyl]piperazine, provides
the desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-[2-cyclohexylethyl]piperazine (1.195 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 94
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.2-[3-pyridylmethylamino]-ethyl
1-(2-[3-pyridylmethylamino]-ethyl)-piperazine (2.20 g, 10 mmol) is
dissolved in 20 mL of dioxane:water (1:1) mixture and
2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (2.46 g, 10
mmol) is added. The mixture is then stirred until no starting
material is detected on thin layer chromatography. The obtained
mixture is fractionally separated by silica gel chromatography,
followed by RP-HPLC to obtain
1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine.
Following the procedure of Example 6, but replacing
1-benzylpiperazine with
1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol),
1-(2-[N-tert-butoxycarbonyl-3-pyridylmethylamino]-ethyl)-piperazine
(1.951 g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10
mL of methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5, followed by a carefully
deprotection of N-tert-butoxycarbonyl group with 10%
trifluoroacetic acid to obtain the pure title compound.
EXAMPLE 95
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=1; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.3-chloropropyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with 1-(3-chloropropyl)homopiperazine, provides
the desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
1-(3-chloropropyl)homopiperazine (1.021 g, 6.09 mmol), and
triethylamine (0.85 mL, 6.09 mmol) in 10 mL of methylene chloride
are used. The obtained product (1.0 g) is treated with 48%-HF (4
mL) in 35 mL of acetonitrile in the procedure described in Example
5 to obtain the pure title compound.
EXAMPLE 96
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=1; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1
.dbd.5-iodonaphthalene-1-sulfonyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with
1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine,
provides the desired compound. The product of Example 3 (2.1 g,
2.03 mmol),
1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine (2.535
g, 6.09 mmol), and triethylamine (0.85 mL, 6.09 mmol) in 10 mL of
methylene chloride are used. The obtained product (1.0 g) is
treated with 48%-HF (4 mL) in 35 mL of acetonitrile in the
procedure described in Example 5 to obtain the pure title
compound.
EXAMPLE 97
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=2; n=1; R.sup.2
.dbd.R.sup.2'.dbd.R.sup.3 .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with heptamethyleneimine, provides the desired
compound. The product of Example 3 (2.1 g, 2.03 mmol),
heptamethyleneimine (769 .mu.L, 6.09 mmol), and triethylamine (0.85
mL, 6.09 mmol) in 10 mL of methylene chloride are used. The
obtained product (1.0 g) is treated with 48%HF (4 mL) in 35 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 98
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 and R.sup.105 taken together
form an oxo group
Methylsulfide-chlorine complex was prepared by adding oxalyl
chloride (0.32 g) into a stirred solution of dimethylsulfoxide
(0.44 g) in methylene chloride (4 mL) and stirring at -70.degree.
C. for 0.5 hours. The solution of the complex was added in slow
dropwise fashion into a stirring solution of ascomycin (1.6 g) in
methylene chloride (5 mL) at -70.degree. C. After stirring for 0.25
hours, triethylamine (1.4 g) was added at -70.degree. C. Stirring
was continued at -70.degree. C. for 0.5 hours and then at room
temperature for 1 hour. The reaction mixture was then diluted with
ether (100 mL), washed with 1N HCl (aq) (2.times.30 mL), saturated
brine (30 mL), dried over magnesium sulfate and solvent removed.
The product was purified on silica gel (70 g) with ether elution.
Yield: 0.95 g; MS (FAB) m/z: M+H=790.
EXAMPLE 99
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.105 .dbd.OH
Lithium tri-t-butoxyaluminum hydride (0.2 mL, 1 M in THF) was added
slowly into a stirred solution of the product of Example 48 (0.056
g) in dry THF (1 mL) at -70.degree. C. under nitrogen. After
stirring at -70.degree. C. for 3 hours, it was partitioned between
ether (50 mL) and 1N HCl (10 mL). The organic phase was dried over
magnesium sulfate, the solvent was removed and the product purified
by prep TLC (35% acetone in hexanes). Yield: 0.025 g; MS (FAB) m/z:
M+K=830.
EXAMPLE 100
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.105
.dbd.O-trifluoromethanesulfonyl
The product of Example 99 (4.0 g, 4.42 mmol) is dissolved in 20 mL
of methylene chloride at 0.degree. C. pyridine (3.57 mL, 44.2
mmol), followed by trifluoromethanesulfonic acid anhydride (0.74
mL, 4.42 mmol) are carefully added to the reaction mixture. It is
stirred at 0.degree. C. for 20 minutes and the solvent is removed.
Ethyl acetate (50 mL) is added to the residue. The organic layers
are washed with brine, saturated NaHCO.sub.3 (20 mL.times.3), brine
(20 mL), 10%--NaHSO.sub.4 (20 mL.times.3), brine (20 mL.times.3)
and dried over anhydrous sodium sulfate. After the solvent is
removed, the title compound is obtained.
This compound was used for the displacement reaction without
further purification and characterization.
EXAMPLE 101
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; m=0; n=1; R.sup.3 .dbd.R.sup.4
.dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.methyl; R.sub.105 .dbd.H
The product of Example 100 (2.1 g, 2.03 mmol) is dissolved in 10 mL
of freshly distilled methylene chloride, 1-methylpiperazine (1.24
mL, 10.15 mmol) and triethylamine (0.85 mL, 6.09 mmol) are added,
and the reaction is then stirred at 50.degree. C. for 5 hours and
at room temperature for one over night. The reaction mixture is
directly poured onto silica gel column and eluted to obtain pure
title compound.
EXAMPLE 102
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102 and
R.sup.103 taken together form a bond; R.sup.104 .dbd.OH; R.sup.105
.dbd.H
Ascomycin (10 g, 12.6 mmol) and pyridinium p-toluene sulfonate (1
g, 3.98 mmol) were dissolved in 200 mL of toluene and stirred at
70.degree. C. for one over night. Solvent was removed and the
residue was purified by silica gel column chromatography, eluting
with 5-10% acetone in hexane. 8.89 g of the title compound was
isolated in 91% yield. MS (FAB) m/z: M+K=812.
EXAMPLE 103
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; R.sup.105 H
The product of Example 102 (2.2 g, 2.8 mmol) was hydrogenated in
the presence of 5% rhodium on alumina (220 mg) in 100 mL of ethanol
at room temperature for 1 hour. After faltered, the filtrate was
concentrated in vacuo to obtain the title compound in quantitative
yield. The obtained product was then loaded on silica gel column,
and eluted with 5-10% acetone in hexane to obtain the pure title
compound in 75-80 yield. MS (FAB) m/z: M+K=814.
EXAMPLE 104
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.n-propyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.OH; R.sup.105 .dbd.H
FK-506 (150 mg, 0.2 mmol) was dissolved in 6 mL of ethyl acetate
and 30 mg of 10%-palladium on charcoal was added. It was
hydrogenated at room temperature for 20 minutes under one
atmosphere pressure. After filtered the catalyst, the solvent was
evaporated to dryness to yield 150 mg of crude product, which was
then purified by silica gel column chromatography, eluting with
chloroform: acetone (5:1) mixture. 114 mg of the pure title
compound was isolated in 76% yield. MS (FAB) m/z: M+K=844.
EXAMPLE 105
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.4 .dbd.R.sup.5 H; R.sup.3
.dbd.hydroxymethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (+/-)-2-piperidinemethanol, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
(+/-)-2-piperidinemethanol (700 mg, 6.08 mmol), and triethylamine
(0.846 mL, 6.08 mmol) in 10 mL of methylene chloride were used. The
reaction was carried out at 45.degree. C. for one over night with
stirring. The reaction mixture was purified on silica gel cloumn.
After the column was washed with 10% acetone in hexane to remove
by-products, the compound was eluted with 10% methanol in methylene
chloride to obtain the product (850 mg) in 42% yield. MS (FAB) m/z:
M+K=1041, M+H=1003. The obtained product (850 mg, 0.85 mmol) was
treated with 48%-HF (3.5 mL) in 35 mL of acetonitrile and then
purified in the procedure described in Example 5 to obtain the pure
title compound (290 mg) in 39% yield. MS (FAB) m/z: M+K=927,
M+H=889. mp=98.degree.-100.degree. C.
EXAMPLE 106
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.3 .dbd.R.sup.5 .dbd.H; R.sup.4
.dbd.hydroxymethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (+/-)-3-piperidinemethanol, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
(+/-)-3-piperidinemethanol (700 mg, 6.08 mmol), and triethylamine
(0.846 mL, 6.08 mmol) in 10 mL of methylene chloride were used. The
reaction was carried out at 45.degree. C. for one over night with
stirring. The reaction mixture was purified on silica gel cloumn.
After the column was washed with 10% acetone in hexane to remove
by-products, the compound was eluted with 10% methanol in methylene
chloride to obtain the product (1.34 g) in 66% yield. MS (FAB) m/z:
M+K=1041, M+H=1003. The obtained product (1.34 g, 1.33 mmol) was
treated with 48%-HF (4 mL) in 40 mL of acetonitrile and then
purified in the procedure described in Example 5 to obtain the pure
title compound (247 mg) in 20% yield. MS (FAB) m/z: M+K=927,
M+H=889. mp=110.degree.-112.degree. C.
EXAMPLE 107
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3
.dbd.hydroxyethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (+/-)-2-piperidine-ethanol, provided the
desired compound. The product of Example 3 (2.1 g, 2.03 mmol),
(+/-)-3-piperidine-ethanol (785 mg, 6.08 mmol), and triethylamine
(0.0.846 mL, 6.08 mmol) in 10 mL of methylene chloride were used.
The reaction was carried out at 45.degree. C. for one over night
with stirring. The reaction mixture was purified on silica gel
cloumn. After the column was washed with 10% acetone in hexane to
remove by-products, the compound was eluted with 10% methanol in
methylene chloride to obtain the product (1.32 g) in 64% yield. MS
(FAB) m/z: M+H=1017. The obtained product (1.3 mg, 1.28 mmol) was
treated with 48%-HF (4 mL) in 40 mL of acetonitrile and then
purified in the procedure described in Example 5 to obtain the pure
title compound (6 1 5mg) in 53% yield. MS (FAB) m/z: M+K =941,
M+H=903. mp=85.degree.-90.degree. C.
EXAMPLE 108
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.3 .dbd.R.sup.5 .dbd.H; R.sup.4
.dbd.hydroxy
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (+/-)-3-hydroxypiperidine, provided the
desired compound. The product of Example 3 (2.0 g, 1.93 mmol),
(+/-)-3-hydroxypiperidine(0.585 ml, 5.79 mmol), and triethylamine
(0.672 mL, 4.83 mmol) in 10 mL of methylene chloride were used. The
reaction was carried out at 45.degree. C. for one over night with
stirring. The reaction mixture was purified on silica gel cloumn.
After the column was washed with 10% acetone in hexane to remove
by-products, the compound was eluted with 10% methanol in methylene
chloride to obtain the product (1.11 g) in 58% yield. MS (FAB) m/z:
M+H=989. The obtained product (1.10 g, 1.113 mmol) was treated with
48%-HF (4 mL) in 40 mL of acetonitrile and then purified in the
procedure described in Example 5 to obtain the pure title compound
(149 mg) in 15% yield. MS (FAB) m/z: M+K.sup.+ =913, M+H.sup.+
=889.
EXAMPLE 109
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=0; n=1; R.sup.2
.dbd.R.sup.2' .dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.3
.dbd.hydroxymethyl
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (S)-(+)-2-pyrrolidine methanol, provided
the desired compound. The product of Example 3 (2.0 g, 1.93 mmol),
(S)-(+)-2-pyrrolidine methanol (0.571 ml, 5.79 mmol), and
triethylamine (0.538 mL, 3.86 mmol) in 10 mL of methylene chloride
were used. The reaction was carried out at 45.degree. C. for one
over night with stirring. The reaction mixture was purified on
silica gel cloumn. After the column was washed with 10% acetone in
hexane to remove by-products, the compound was eluted with 10%
methanol in methylene chloride to obtain the product (1.24g) in 65%
yield. MS (FAB) m/z: M+H=989. The obtained product (1.04 g, 1.06
mmol) was treated with 48%-HF (4 mL) in 40 mL of acetonitrile and
then purified in the procedure described in Example 5 to obtain the
pure title compound (212 mg) in 23% yield. MS (FAB) m/z: M+K.sup.+
=913, M+H.sup.+ =875. mp=75.degree.-95.degree. C.
EXAMPLE 110(a)
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.013 .dbd.R.sup.104 .dbd.dimethylthexylsilyl;
R.sup.105 .dbd.H
Ascomycin (1 g, 1.26 mmol) was dissolved in a solution of imidazole
(0.86 g, 12.6 mmol) in dry N,N-dimethylformamide (10 mL) and
dimethylthexylchlorosilane (1.24 g, 6.3 mmol) was added in portions
and stirred at room temperature for 3 days. Diethylether (100 ml)
was added to the reaction mixture, and the organic layer was washed
with saturated ammonium chloride aqueous solution (30 mL.times.3),
10%--NaHSO.sub.4 (30 mL.times.3), brine (30 mL), saturated
NaHCO.sub.3 (30 mL.times.3), and brine (30 mL.times.3). After dired
over MgSO4, solvent was removed in vacuo and the solid residue was
purified by silica gel chromatography (569 mg), followed by HPLC
eluting with 10% acetone in hexane providing the title compound
(372.5 mg) in 27% yield. MS (FAB) m/z: M+K.sup.+ =1114.
mp=100.degree.-104.degree. C.
EXAMPLE 110(b)
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.dimethylthexyl-silyloxy;
R.sup.105 .dbd.H
During the purification of the crude product of Example 110-(a) by
silica gel column chromatography, pure-mono substituted title
compound (456 mg) was isolated in 39% yield MS (FAB) m/z: M+K.sup.+
=972. mp=92.degree.-94.degree. C.
EXAMPLE 111
Formula I; R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.dimethylthexylsilyloxy; R.sup.104 .dbd.OH;
R.sub.10 .dbd.H
To a solution of 48% hydrogen fluoride aqueous solution (0.2 mL)
was added Example 110-(a) (0.2 g, 0,186 mmol) in acetonitrile (10
mL), and the mixture was stirred at room temperature for 30
minutes. It was cooled to 0.degree. C. in an ice bath, and solid
NaHCO.sub.3 was added to the reaction mixture. It was stirred for 1
hour and solid was removed by filtration. Acetonitrile was removed,
and the crude title compound was purified by silica gel column
chromatography. 140 mg (81%) of pure compound was obtained. MS
(FAB) m/z: M+K =972.
EXAMPLE 112
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=1; n=0; R.sup.3 and
R.sup.5 taken together.dbd.CH2; R.sup.1 .dbd.benzyl; R.sup.4
.dbd.H
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1
]heptane, provides the desired compound. The product of Example 3
(2.0 g, 1.93 mmol), (1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane
(1.09 g 5.79 mmol), and triethylamine (0.672 mL, 4.83 mmol) in 10
mL of methylene chloride are used. The obtained product is treated
with 48%-HF (4 mL) in 40 mL of acetonitrile in the procedure
described in Example 5 to obtain the pure title compound.
EXAMPLE 113
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=1; n=0; R.sup.3 and
R.sup.5 taken together.dbd.CH2; R.sup.4 .dbd.H; X=oxygen
Following the procedure of Example 6, but replacing
1-benzylpiperazine with (1S,4S)-2-oxa-5-azabicyclo[2.2.1 ]heptane,
provides the desired compound. The product of Example 3 (2.0 g,
1.93 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane (587 mg, 5.79
mmol), and triethylamine (0.538 mL, 3.86 mmol) in 10 mL of
methylene chloride are used. The obtained product is treated with
48%-HF (4 mL) in 30 mL of acetonitrile in the procedure described
in Example 5 to obtain the pure title compound.
EXAMPLE 114
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=1; n=0; R.sup.3 and
R.sup.5 .dbd.H; X.dbd.oxygen; R.sup.4
.dbd.N,N-dimethylaminomethyl
2-[(N,N-dimethylamino)methyl]morpholine is prepared by the method
described in the literature (Araki, K. et. al., J. Med. Chem. 36:
1356-1363 (1993)). Following the procedure of Example 6, but
replacing 1-benzylpiperazine with
2-[(N,N-dimethylamino)methyl]morpholine, provides the desired
compound. The product of Example 3 (2.0 g, 1.93 mmol),
2-[(N,N-dimethylamino)methyl]morpholine (5.79 mmol), and
triethylamine (0.672 mL, 4.83 mmol) in 10 mL of methylene chloride
are used. The obtained product is treated with 48%HF (4 mL) in 40
mL of acetonitrile in the procedure described in Example 5 to
obtain the pure title compound.
EXAMPLE 115
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H;R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=1; n=0; R.sup.3 and
R.sup.5 .dbd.H; X.dbd.oxygen; R.sup.4 .dbd.2-acetamidoethyl
2-(2-Acetamidoethyl)morpholine is prepared by the method described
in the literature (Araki, K. el. al., J. Med. Chem. 36:1356-1363
(1993)). Following the procedure of Example 6, but replacing
1-benzylpiperazine with 2-(2-acetamidoethyl)morpholine, provides
the desired compound. The product of Example 3 (2.0 g, 1.93 mmol),
2-(2-acetamidoethyl)morpholine (5.79 mmol), and triethylamine
(0.538 mL, 3.86 mmol) in 10 mL of methylene chloride are used. The
obtained product is treated with 48%-HF (4 mL) in 30 mL of
acetonitrile in the procedure described in Example 5 to obtain the
pure title compound.
EXAMPLE 116
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H;R.sup.103 .dbd.OH; R.sup.104 .dbd.H; m=1; n=0; R.sup.3 and
R.sup.5 .dbd.H; X.dbd.oxygen; R.sup.4
.dbd.2-[(ethoxycarbonyl)amino]methyl
2-{[(Ethoxycarbonyl)amino]methyl}morpholine is prepared by the
method described in the literature (Araki, K. et. al.,J. Med. Chem.
36:1356-1363 (1993)). Following the procedure of Example 6, but
replacing 1-benzylpiperazine with
2-{[(ethoxycarbonyl)amino]methyl}morpholine, provides the desired
compound. The product of Example 3 (2.0 g, 1.93 mmol),
2-{[(ethoxycarbonyl)amino]methyl }morpholine (5.79 mmol), and
triethylamine (0.672 mL, 4.83 mmol) in 10 mL of methylene chloride
are used. The obtained product is treated with 48%-HF (4 mL) in 40
mL of acetonitrile in the procedure described in Example 5 to
obtain the pure title compound.
EXAMPLE 117
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.H; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyrimidyl
The product of Example 81 (5 mmol) is dissolved in 25 mL of
methylene chloride. This is added to a solution of 5 mL of
methylene chloride containing tert-butyl hydroperoxide in
2,2,4-trimethylpentane (6.65 mL, 20 mmol) and selenium oxide (830
mg, 7.5 mmol). The reaction is monitored by thin layer
chromatography. The mixture is stirred at room temperature until
the starting material is disappeared. Solvents are removed and an
approximately 100 mL of ethyl acetate is added to the residue. The
ethyl acetate layer is washed with brine, dried over anhydrous
sodium sulfate. Purification of the title compound is carried out
by high performance liquid chromatography.
EXAMPLE 118
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.104 .dbd.H; m=0; n=1; R.sup.3 .dbd.R.sup.4
.dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyrimidyl
A solution of the product of example 117 (100 mg) in 1 mL of
methylene chloride is cooled to -78.degree. C. in a dry
ice/isopropanol bath. To this stirred solution, diethylaminosulfur
trifluoride (10 .mu.L) is added. After 3 minutes, saturated sodium
bicarbonate (1 mL) is added followed by 5 mL of ethyl acetate and
the mixture is warmed to room temperature. Extraction from ethyl
acetate, drying over anhydrous magnesium sulfate and purification
by high performance liquid chromatography gives the pure title
compound.
EXAMPLE 119
Formula I: R.sup.100 .dbd.H; R.sup.101 .dbd.ethyl; R.sup.102
.dbd.H; R.sup.103 .dbd.H; R.sup.104 .dbd.H; m=0; n=1; R.sup.3
.dbd.R.sup.4 .dbd.R.sup.5 .dbd.H; R.sup.1 .dbd.2-pyrimidyl
A solution of the product of example 117 (100 mg) in 1 mL of
pyridine is cooled to 0.degree. C. in an ice bath. To this stirred
solution, N,N-dimethylaminopyridine (3 .mu.g), followed by acetic
acid anhydride (20 .mu.l) are added. After stirred at 0.degree. C.
for 5 hours, it is stirred at room temperature for one over night.
Extraction from ethyl acetate, drying over anhydrous magnesium
sulfate and purification by high performance liquid chromatography
gives the pure title compound.
EXAMPLE 120
In Vitro Assay of Biological Activity
The immunosuppressant activity of the compounds of the present
invention was determined using the human mixed lymphocyte reaction
(MLR) assay described by Kino, T. et al. in Transplantation
Proceedings XIX(5):36-39, Suppl. 6 (1987), incorporated herein by
reference. The results of the assay, shown below in Table 1,
demonstrate that the compounds tested are effective
immunomodulators at sub-micromolar concentrations.
TABLE 1 ______________________________________ Ex. # IC.sub.50 (M)
Ex. # IC.sub.50 (M) ______________________________________ 5 <1
.times. 10.sup.-6 28 <1 .times. 10.sup.-6 7 <1 .times.
10.sup.-6 31 <1 .times. 10.sup.-6 9 <1 .times. 10.sup.-6 38
<1 .times. 10.sup.-6 11 <1 .times. 10.sup.-6 39 <1 .times.
10.sup.-6 12 <1 .times. 10.sup.-6 44 <1 .times. 10.sup.-6 13
<1 .times. 10.sup.-6 58 <1 .times. 10.sup.-6 14 <1 .times.
10.sup.-6 61 <1 .times. 10.sup.-6 15 <1 .times. 10.sup.-6 62
<1 .times. 10.sup.-6 16 <1 .times. 10.sup.-6 67 <1 .times.
10.sup.-6 17 <1 .times. 10.sup.-6 76 <1 .times. 10.sup.-6 18
<1 .times. 10.sup.-6 105 <1 .times. 10.sup.-6 19 <1
.times. 10.sup.-6 106 <1 .times. 10.sup.-6 20 <1 .times.
10.sup.-6 107 <1 .times. 10.sup.-6 21 <1 .times. 10.sup.-6
108 <1 .times. 10.sup.-6 22 <1 .times. 10.sup.-6 109 <1
.times. 10.sup.-6 27 <1 .times. 10.sup.-6
______________________________________
It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will
be apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof.
* * * * *